ACCP Unveils Updated Thrombosis Close Call Guidelines

B Y M I R I A M E . T U C K E R

Else vier Global Medical Ne ws

AT L A N TA — All adults withasthma should now receivepneumococcal immunization,the Advisory Committee on Im-munization Practices of theCenters for Disease Control andPrevention voted June 25 at itssummer meeting.

The vote adds adults aged 18-64 years with asthma to the listof individuals considered at in-creased risk for invasive pneu-mococcal disease (IPD).

Current Advisory Committeeon Immunization Practices(ACIP) recommendations callfor use of the 23-valent poly-saccharide pneumococcal vac-cine (PPSV23) in all adults age65 years and older and in high-risk individuals age 2-64 years.Among the latter group are

those with chronic pulmonaryconditions including chronic ob-structive pulmonary disease(COPD) and emphysema(MMWR 1997;46[RR-8]:1-24).

Asthma was not included atthe time that recommendationwas made because not enoughdata were available about therisk of IPD among individualswith asthma, except for thosewith long-term use of systemiccorticosteroids. Such data have

since become available, andwere reviewed for the commit-tee by Dr. Pekka Nuorti of theCDC’s National Center for Im-munization and RespiratoryDiseases.

In a nested case-control studyof persons age 2-49 years en-rolled in Tennessee’s Medicaidprogram (TennCare) for at least1 year during 1995-2002, each

Presorted StandardU.S. Postage

PAIDPermit No. 384Lebanon Jct. KY

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ACCP UnveilsUpdated Thrombosis

Guidelines

B Y B E T S Y B AT E S


Sweeping new clinicalguidelines issued by theAmerican College of

Chest Physicians provide updat-ed recommendations on how toprevent and manage thrombosisin surgical patients and specialrisk groups, including pregnantwomen, children, obese pa-tients, and patients with pros-thetic heart valves or a history ofcardiovascular disease or stroke.

Separate sections address pa-tients with inherited throm-bophilias and treatment of deepvein thrombosis and pul-monary embolism.

Unveiled in the June issue ofCHEST, the guidelines repre-sent the first major revision inthe recommendations since2004. Compiled by more than 90experts, the 700 recommenda-tions run more than 1,000 pages,although a concise, 38-page ex-ecutive summary is available(Chest 2008;133:71S-109S).

In accordance with many

new clinical guidelines, gradesare assigned to each recom-mendation or suggestion, basedon the quality of the availableevidence and the strength ofthe recommendation.

Among the most noteworthyrecommendations is a renewedcall for venous thromboem-bolism (VTE) prophylaxis ofmost hospitalized patients.

“For every general hospital,we recommend that a formal,active strategy that addressesthe prevention of VTE be de-veloped . . . in the form of a written, institution-wide throm-bo-prophylaxis policy,” theguidelines state.

Computer decision supportsystems, preprinted orders, andperiodic audits and feedbackmechanisms are advocated bythe committee, while “passivemethods” such as educationalmeetings and handouts aredeemed inadequate as stand-alone strategies to increase ad-herence to thromboprophylaxis.

PET/CT Accurate WhenStaging Early NSCLC B Y F R A N L O W RY


C H I C A G O — In patients withearly-stage, biopsy-proven non–small cell lung cancer, thecombination of 18fluorode-oxyglucose (FDG)–PET/CT andcranial imaging can reduce stage-inappropriate surgeries by pro-viding more accurate stagingthan conventional imaging, a ran-domized trial suggests.

Investigators randomized 163patients with biopsy-provennon–small cell lung cancer whowere felt to have resectable disease(on the basis of physical exami-nation, computed tomography ofthe chest, or a chest x-ray) to con-ventional staging (CT scan of theabdomen, bone scan, and brainimaging by CT or MRI), or to

positron emission tomographystaging (whole-body PET/CTscan and cranial imaging by CT orMRI), Dr. Donna E. Maziak,FCCP, reported at the annualmeeting of the American Societyof Clinical Oncology.

Of the patients who were ran-domized to whole-body PET/CT,23 (14%) were correctly upstaged,which prevented stage-inappro-priate surgery, compared with 11 (7%) of 157 patients random-ized to conventional imaging (P = .046). The eight-center trial also found that conven-tional imaging erroneously un-derstaged 47 (30%) patients,whereas whole-body PET/CTerroneously understaged 18(11%) patients (P = .00003).

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The results show that PET/CT can replace conventional staging inearly-stage non–small cell lung cancer, said Dr. Donna E. Maziak.

Vaccinate for IPD in Adults With Asthma

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Note: Based on data from the Youth Risk Behavior Survey for students reporting smoking cigarettes on at least 1 day during the 30 days prior to the survey.Source: Centers for Disease Control and Prevention

Smoking Rates of High School Students Falling

V I T A L S I G N S

See Guidelines • page 2

Pulmonary Medicine

Close CallCongress overrides a

presidential veto to prevent the10.6% Medicare physician pay

cut from taking effect. • 3

Critical Care Medicine

Cleaning HouseHow one hospital’s central-line

protocol cut its infection rate to nearly zero. • 6

Pulmonary Perspectives

Gene FactorIn sarcoidosis, the role ofgenetics seems to be only part of the story. • 8

Sleep Medicine

Severe RiskSevere sleep apnea

significantly increased all-cause mortality risk,

according to an Australiancommunity study. • 1 8

I N S I D E

See PET/CT • page 2

First major revision since 2004.

See Vaccinate • page 3

VOL. 3 • NO. 8 • AUGUST 2008

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Hospitals need to have firm policies andenforce them, said Dr. Jack Hirsh, FCCP,professor emeritus of medicine at Mc-Master University and founding director ofthe Henderson Research Center, both inHamilton, Ont.

In the new guidelines, the recommen-dation for VTE prophylaxis has been ex-panded beyond major general,gynecologic, and orthopedic surgeries toinclude bariatric and coronary artery by-pass surgery.

No prophylaxis is recommended forlow-risk patients undergoing laparoscop-ic surgery or knee arthroscopy, or thosetaking long airplane flights.

As expected, the new guidelines reaf-firm the position of the American Collegeof Chest Physicians that aspirin alone isnot sufficient therapy to prevent venousthromboembolism in any patient popula-tion, because more effective alternativesare available, including heparin, low-mol-ecular-weight heparin, and a synthetic, se-lective factor Xa inhibitor, fondaparinux,which was approved by the FDA in 2001.

Many of the guidelines now mentioningfondaparinux as an alternative anticoagulantrate the evidence for its use as 1A, meaning

that the supportive data are strong.The length of recommended postsurgi-

cal prophylaxis has been extended in theguidelines to 28 days (and in some surgeries,35 days) for most general, gynecologic, andorthopedic procedures, noted Dr. Geno J.Merli, chief medical officer of Thomas Jef-ferson University Hospital, Philadelphia.Previously, prophylaxis was generally ad-vised for 2 weeks following surgery.

Among the most pivotal changes in therecommendations are guidelines on pa-tients with atrial fibrillation, managementof pregnant women and children, andtreatment of DVT.� Atrial fibrillation. Antithrombotic ther-apy in patients with atrial fibrillation isawarded the strongest evidence grade (1A),reflecting widespread agreement of find-ings from randomized, controlled trials.

Target international normalized ratioranges, drug choices, and dosages are de-tailed in the new guidelines in the hopesthat primary care physicians will use thedocument to guide therapy, Dr. Hirsh said.

“There is marked underutilization ofwarfarin [in atrial fibrillation patients], notby cardiologists, but by family physicians.The logistics of monitoring are difficult,”he said. As a result, one entire section ad-dresses the nuts and bolts of monitoring. � Pregnant women. Dr. Hirsh identifiednew guidelines for pregnancy as among“the most controversial and, I think, themost important” in the document.

Randomized trials are difficult to con-duct in this population, so most of the rec-ommendations receive a 2C grade thatreflects weak evidence, noted Dr. ShannonM. Bates, who oversaw the chapter onpregnancy issues.

Nonetheless, “a great deal of work hasgone into making sure that our recom-mendations are unbiased and clearly re-flect the available data,” said Dr. Bates,director of the adult hematology residen-cy training program at McMaster Univer-sity Medical Centre in Hamilton, Ont.

Key elements of the pregnancy guide-lines include a recommendation againstroutine prophylaxis other than early mo-bilization in patients undergoing Cesarean

section, and deletion of a previous rec-ommendation advocating antithrombotictherapy in women with pregnancy com-plications and a known inherited hyperco-agulable state.� Children. Greatly expanded guidelines“pretty well cover every conceivablethrombotic issue” in neonates and chil-dren, Dr. Hirsh noted.

Stroke is 1 of the 10 leading causes ofdeath in childhood, but it is difficult to di-agnose and predict based on risk factors.Therefore, the new guidelines recommendthat any child with arterial ischemic strokereceive initial antithrombotic therapy un-til the underlying causes are understood,followed by maintenance therapy to pre-vent recurrence.

Detailed sections offer guidelines on theprevention of thrombotic events in chil-dren with congenital heart disease, in-cluding sections on ventricular assistdevices and prosthetic heart valves.� Treatment of DVT. The guidelines of-fer two options—one monitored and oneunmonitored—for subcutaneous heparinadministration for acute DVT, Dr. Merlisaid in an interview.

The first regimen calls for an initialdose of 17,500 U or a weight-adjusteddose of about 250 U/kg every 12 hours,with the dose adjusted to achieve andmaintain an activated partial thrombo-plastin time (aPTT) prolongation thatcorresponds to plasma heparin levels of0.3-0.7 IU/mL anti-Xa activity whenmeasured 6 hours after injection (ratherthan beginning therapy with the smallerinitial dose).

The second option is a fixed dose, un-monitored regimen that calls for an initialdose of 333 U/kg followed by a twice-dai-ly dose of 250 U/kg.

The guidelines also suggest for the firsttime the use of catheter-directed throm-bolysis with thrombus fragmentationand/or aspiration in “selected patientswith extensive acute proximal DVT whohave a low risk of bleeding,” but advocatethis pharmacomechanical approach only if“appropriate expertise and resources areavailable.” ■

ThrombosisGuidelines • from page 1

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2 NEWS CHEST P H Y S I C I A N • AUGUST 2008

“These results show that [whole-body PET/CT] can replace conven-tional staging in early-stage non–smallcell lung cancer,” explained Dr. Maziakof the University of Ottawa.

The study was conducted by the On-tario Clinical Oncology Group, andfunded by the Ontario Ministry ofHealth and the Canadian Institutes ofHealth Research.

The patients were matched for age(mean 67 years), Eastern CooperativeOncology Group (ECOG) performancestatus, and smoking status. Half of thestudy population was female.

Discussant Dr. Reginald F. Munden,chair of the department of radiology at the University of Alabama at Birm-ingham, said the conclusion that whole-body PET/CT can replace con-ventional staging of non–small celllung cancer has to be qualified.

He reminded delegates that the CTbeing done with PET must be done atfull inspiration, so that small lesions arenot missed.

“The lung windows have to be done in a diagnostic mode; otherwise,you cannot replace conventional CTwith a routine PET/CT,” Dr. Mundencautioned.

He added that the degree to whichfutile surgeries can be reduced with theuse of PET/CT remains debatable.

“I suspect the reduction in futile surg-eries probably has as much to do with local practice as it does with theimaging itself,” he said.

“As we know, some surgeons wouldprefer to do mediastinoscopy on every-one,” Dr. Munden added.

“Most of the studies seem to suggestthere is a reduction, but the question is,Is it a significant reduction or not?” hesaid.

Neither Dr. Maziak nor Dr. Mun-den disclosed any relevant conflicts ofinterest. ■

NSCLC StagingPET/CT • from page 1

I N T H I S I S S U E

News From the College • 1 0

Critical Care CommentaryWhat recent initiatives reveal about the optimal staffing mix

of physicians and midlevel providers in the ICU. • 1 3

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AUGUST 2008 • CHEST P H Y S I C I A N PULMONARY MEDICINE 3

case of IPD was matched with 10 con-trols of the same age without IPD. A to-tal of 635 persons with IPD and 6,350controls was identified, of whom 114(18%) and 516 (8%), respectively, hadasthma. The adjusted odds ratio for IPDamong those with asthma, comparedwith controls, was 2.4, which the authorsconcluded suggests that asthma is an in-dependent risk factor for IPD (N. Engl.J. Med. 2005;352:2082-90).

Despite data from another case-con-trol study of older veterans with eitherasthma or COPD which suggested thatthose with asthma were not at signifi-cantly increased risk for IPD-related hos-pitalizations ( J. Gen. Intern. Med.2007;22:62-7), the committee agreedwith the decision made by an ACIPworking group prior to the meeting thatthe bulk of the data suggests that asth-ma does increase the IPD risk.

Dr. Sandra Fryhofer, acting liaison toACIP from the American College ofPhysicians (ACP), agreed.

“Asthma definitely increases the risk ofsevere pneumococcal infections. Thenew recommendation includes asthmawith other chronic lung diseases. That’sa good thing,” she said in an interview.

Echoing a point made by several ACIPmembers during the discussion, she alsonoted that in adult patients it is often dif-ficult to distinguish between asthma,COPD, and chronic bronchitis.

“I think this is going to make the rec-ommendations easier to follow [and] en-sure that the right people get thevaccine,” said Dr. Fryhofer, a formerACP president who practices internalmedicine in Atlanta.

Also during the same session at theACIP meeting, the committee voted toclarify language that had been misinter-preted by some providers as suggestingrevaccination should take place every 5years in individuals for whom PPSV23 isrecommended.

In fact, routine revaccination is not rec-ommended for most people. A seconddose of vaccine—but no more—is rec-ommended at 5 years after the first dosefor patients with functional or anatom-ic asplenia or immunocompromisingconditions.

The committee opted not to recom-mend lowering the age of universalPPSV23 immunization from 65 yearsand older to 50 years, primarily becausesuch a move would require a change inthe schedule for revaccination, for whichfew data are available.

In addition, the risk of IPD among individuals aged 50-64 years has de-creased in recent years because of rou-tine use of the 7-valent pneumococcalconjugate vaccine (PCV7) in infants.The overall IPD rates in adults havedropped 18%-39% since the pre-PCV7era, Dr. Nuorti said. ■

ACIP Makes RecommendationsVaccinate • from page 1

B Y K E R R I WA C H T E R


C H I C A G O — Following 5 years of im-proved survival with cisplatin-based adju-vant chemotherapy for resected non–smallcell lung cancer, investigators were sur-prised to find more late mortality in treat-ed patients, compared with thoserandomized to observation in a largephase III study.

“We observed more deaths after 5 yearsin the chemotherapy arm, comparedwith the control arm,” said Dr. ThierryLe Chevalier at the annual meeting of theAmerican Society of Clinical Oncology,where he presented long-term data fromthe International Adjuvant Lung CancerTrial (IALT).

Adjuvant cisplatin-based chemothera-py produced a significant survival advan-tage during the first 5 years (hazard ratioof death 0.86, P = .01), but treated patientswere more likely to die during years 6-8,compared with control patients random-ized to observation (hazard ratio of death1.45, P =.04).

In the chemotherapy arm, 495 deaths oc-curred before 5 years and 83 deaths after-ward, whereas the control group had 534deaths before 5 years and 56 afterward.

Of note, over 8 years non–lung cancermortality was greater in the chemotherapy

arm (hazard ratio of 1.34, P = .06). After5 years non–lung cancer deaths becamemore than twice as common in thechemotherapy arm: 25 vs. 10 in the con-trol group.

From 1995 to 2001, the IALT Collabo-rative Group randomized 1,867 patientswith resected, pathologically document-ed stage I, II, or III non–small cell lungcancer (NSCLC) at 148 centers in 33countries—932 patients to adjuvant cis-platin (Platinol)–based chemotherapy and935 to observation alone.

Thoracic radiotherapy of 60 Gy or less was optional (predefined by Nstage at each center). Median follow-upwas 7.5 years with 97% of patients in follow-up.

Centers were allowed to choose cis-platin chemotherapy of 80 mg/m2 every3 weeks for four cycles, 100 mg/m2 every4 weeks for three to four cycles, or 120mg/m2 every 4 weeks for three cycles.

Each center also could choose one ofthe following drugs for combination withcisplatin: 100 mg/m2 etoposide on days 1-3, vinorelbine (Navelbine) 30 mg/m2

weekly, vinblastine (Velban) 4 mg/m2

weekly, or vindesine (Eldisine) 3 mg/m2

weekly.The overall survival rate at 8 years was

38% (578 deaths) in the chemotherapyarm, compared with 37% (590 deaths) in

the control arm (hazard ratio 0.91, P = .10), reported Dr. Le Chevalier, nowvice president of GlaxoSmithKline’s Oncology Medicine Development Cen-tre (a position not related to his role inthe study).

Patients in the chemotherapy arm ex-perienced a significant benefit in disease-free survival at 8 years (hazard ratio 0.88,P = .02) and in less local recurrence at 8years (P = .002).

A total of 181 local recurrences were ob-served in the chemotherapy arm, com-pared with 230 in the control arm.

Adjuvant chemotherapy also was asso-ciated with fewer distant metastases at 8 years.

In all, 338 distant metastases occurredin the chemotherapy arm, comparedwith 378 in the control arm (P = .02). No differences in second malignancieswere observed between the two studyarms.

Dr. Chevalier observed that chemother-apy continues to protect against death af-ter 5 years, but said the reason for theexcess in late mortality is unclear.

He called for more long-term follow-upof patients in adjuvant studies and sug-gested that data be pooled to identify pos-sible predictive factors.

To that end the IALT investigators as-sessed 761 patients for expression ofERCC1, a DNA-repair protein, and foundthat ERCC1 status remained predictivefor a survival benefit from adjuvantchemotherapy at 8 years.

Among those who were ERCC1 negative, there was a significant advantagefor chemotherapy (hazard ratio 0.76).

Among those who were ERCC1 posi-tive, there was a trend toward favoring ob-servation (hazard ratio 1.20).

Discussant Dr. Pieter E. Postmus,FCCP, noted that this represents a declinein the survival benefit of ERCC1-nega-tive tumors.

In an IALT substudy published in 2006, chemotherapy significantly im-proved median 5-year overall survivalamong patients with ERCC1-negativetumors, compared with control pa-tients—47% vs. 39% respectively (hazardratio .065, P = .002) (N. Engl. J. Med.2006;355:983-91).

For those with ERCC1-positive tumors,the control group fared better in terms ofoverall survival, though not significantlyso—46% vs. 40% respectively (hazard ra-tio 1.14, P = .4).

“The beneficial effect of being ERCC1negative is apparently disappearing overtime,” said Dr. Postmus of the departmentof pulmonary disease at Vrije UniversiteitMedisch Centrum, Amsterdam.

“The initial positive effect is due to thelow ERCC1 of the tumor; it’s unclearwhy this benefit decreases at longer fol-low-up,” Dr. Postmus added.

As ERCC1 is responsible for DNA re-pair, he speculated that the possible causemight be more late damage due to chemo-therapy, especially in patients with less re-pair capacity. ■

Adjuvant Cisplatin Leads to Late Mortality in NSCLC

B Y M A RY E L L E N S C H N E I D E R


Washington’s summertime wranglingpaid off for physicians last month as

Congress successfully overrode PresidentBush’s veto of legislation to stop a 10.6%cut to Medicare physician payments.

The legislation (H.R. 6331), which orig-inally passed both the House and Senateby veto-proof mar-gins in early July, ex-tends the 0.5%Medicare pay in-crease in place forthe first half of 2008through the end ofthe year and givesphysicians a 1.1%raise for next year.

Congress financedthe pay increases for physicians in partthrough controversial cuts to Medicare Ad-vantage plans. Officials at America’s HealthInsurance Plans, which represents thehealth insurance industry, estimated thatthe bill will cut nearly $14 billion from theMedicare Advantage plans over the next 5years. The inclusion of those cuts in the billslowed its passage in the Senate and causedPresident Bush to veto the legislation.

The bill also encourages physicians andother providers to use electronic prescribing

by providing incentives to those who e-pre-scribe and imposing penalties on those whodo not. In addition, the bill would delay thefirst round of Medicare’s new competitiveacquisition program until 2009.

Now that H.R. 6331 is law, Medicarecontractors are working to make surephysicians are paid at the correct rate.

However, it may take up to 10 businessdays for some contractors to begin paying

claims at the 0.5%update rates, ac-cording to CMS.Once the local con-tractors start payingclaims at the in-creased rate, theywill go back and re-process any claimspaid at the loweramount.

Most claims will be automatically re-processed, but a few providers may needto contact their local contractor for direc-tion on getting their claims adjusted. Forexample, physicians who have submittedcharges that are lower than the Medicarefee schedule amount will need to contacttheir local contractor, CMS said. In addi-tion, nonparticipating physicians who sub-mitted unassigned claims at the reducednonparticipation amount will need to re-quest an adjustment from the carrier. ■

Congress Reverses MedicareCuts, Extends 0.5% Increase

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4 PULMONARY MEDICINE CHEST P H Y S I C I A N • AUGUST 2008

PPI Therapy Fails to Curb Asthma With Asymptomatic GERD B Y N A N C Y WA L S H


T O R O N T O — Treatment with a protonpump inhibitor did not improve asthmacontrol in patients with poorly controlledasthma and minimal or no symptoms ofgastroesophageal reflux, according to re-sults from a large study presented at an in-ternational conference of the AmericanThoracic Society.

Gastroesophageal reflux disease (GERD)is a common problem in patients withasthma, with small studies reporting aprevalence of reflux in 32%-84% of asth-matics. Proton pump inhibitor (PPI) ther-apy is commonly added to therapy inasthma, adding to the overall cost of treat-ment, but the effect of suppression of gas-tric acid on asthma symptoms remainsunclear, according to Dr. Mario Castro,FCCP, of Washington University School,St. Louis.

Uncertainty about the role of GERD inasthma derives from observations that ap-proximately half of asthmatics withoutsymptoms of GERD have been demon-strated to have abnormal reflux and abouthalf of asthmatics who have abnormal re-flux shown on pH probe studies do not havesymptoms of the disease, Dr. Castro said.

“In any case, certainly GERD symp-toms can mimic symptoms of asthma,and we wanted to know how to distin-guish them and how best to treat them,”he said.

Recent guidelines released by the Na-tional Heart, Lung, and Blood Institute(NHLBI) of the National Institutes ofHealth suggested that, even in the absenceof GERD symptoms, consideration shouldbe given to evaluation and possible treat-ment with PPI for patients with poorlycontrolled asthma. This was a consensus-based recommendation.

In order to gain additional data tostrengthen the recommendation, theStudy of Acid Reflux in Asthma (SARA)was undertaken with funding from theNHLBI and conducted by the AmericanLung Association’s asthma clinical re-search centers, a national 20-center net-work dedicated to improving asthmacare.

“SARA included only patients with min-imal or no symptoms of GERD, becausewe felt that any patient with moderate orsevere GERD should, by definition, be re-ceiving a PPI—and, in this trial, there wasthe possibility that they would receiveplacebo,” Dr. Castro said.

Aside from determining whether PPI

therapy could improve asthma symptomsin those patients, SARA also sought to de-termine whether ambulatory pH probemonitoring could identify patients withasymptomatic GERD who might benefitfrom suppression of gastric acid.

The study design called for a 2- to 8-week run-in period, during which the pa-tients underwent esophageal pH probemonitoring and, if not contraindicated,methacholine challenge testing. The pa-tients then were randomly assigned to re-ceive esomeprazole, 40 mg/day, alongwith stable doses of inhaled cortico-steroids (equivalent to at least 400 mg flu-ticasone/day) and long-acting β-agonists ifneeded.

Poorly controlled asthma was defined astwo or more occasions of a 30% or greaterdecline in peak expiratory flow from base-line, the need for oral prednisone, the re-quirement for acute intervention such asan emergency department visit, or theneed for more than four puffs of rescuemedication.

Another investi-gator, Dr. W. Ger-ald Teague of thepediatric asthmacenter at EmoryUniversity, Atlanta,described the base-line characteristicsof the participatingpatients.

“A total of 412 patients were random-ized; but, unfortunately, nature inter-vened, and the data from 10 patients werelost in Hurricane Katrina,” Dr. Teaguesaid. Of the remaining patients, 199 re-ceived placebo and 203 received es-omeprazole.

Overall, the groups were comparable.Mean age was 42 years, and 50% werewhite and 38% were black. In the placebogroup, 28% were male and 20% were for-mer smokers. In the esomeprazole group,36% were male and 15% were formersmokers.

About half of the patients in both studygroups had required the use of rescuemedications during the previous year, andthe same number had required courses oforal prednisone.

Asthma control also was found to beequivalent in the two groups, with a meanAsthma Control Questionnaire (ACQ)score of 1.9 in the placebo group and 1.8in the PPI group.

Lung function also was comparable,with a forced expiratory volume in 1 sec-ond (FEV1) at 78% of predicted in theplacebo group and 76% of predicted inthe esomeprazole group. There were nodifferences in post-albuterol response,forced vital capacity, or bronchial hyper-responsiveness.

On pH probe testing, 40% of patients inboth groups were positive for GERD.

“We were surprised, but when baselineasthma characteristics were analyzed ac-cording to whether or not patients werepositive for GERD on pH probe testing,there was very little effect,” Dr. Teaguesaid.

In both GERD and non-GERD groups,80% of patients had required rescue med-icine, ACQ scores were 1.9, and Asthma

Quality of Life scores were 4.6, he re-ported.

The study results then were summa-rized by Dr. John G. Mastronarde, who isa pulmonologist at Ohio State UniversityMedical Center, Columbus, and director ofthe university’s asthma center.

“Overall, we saw no treatment effect ineither group,” Dr. Mastronarde said. Thenumber of episodes of decrease in peakflow was 1.7/person per year in the place-bo group and 2.1/person per year in theesomeprazole group. The number ofepisodes requiring urgent care was 0.7 inthe placebo group and 0.6 in the es-omeprazole group.

Some studies have suggested that cer-tain subgroups, such as patients withepisodes of nocturnal awakening andthose with a body mass index greaterthan 30 kg/m2, might respond to PPItreatment.

However, those were no different be-tween the placebo and active treatment

groups, he said.Lung function asmeasured on FEV1,peak flow, and testsof bronchial hyper-responsiveness alsoshowed no effects oftreatment, nor didpat ient-centeredoutcomes such asACQ scores, even

among patients who had positive pHprobe tests, said Dr. Mastronarde.

“In summary, asymptomatic GERD iscommon in patients with poorly controlledasthma, but PPI therapy with esomepra-zole does not improve asthma control orlung function in patients with minimal orabsent symptoms of GERD,” he said.

“Ambulatory pH probe testing did notseem to identify any subgroups of patientswho might benefit from PPI therapy interms of asthma control,” he added.

“We think these results are pretty sig-nificant,” Dr. Mastronarde added.

“The NIH guidelines suggest that weconsider evaluation and treatment in pa-tients with poorly controlled asthma onadequate controllers even without symp-toms of GERD, but this study would sug-gest that PPI therapy has no effect oncontrol and is not indicated,” noted Dr.Mastronarde.

“Also, there doesn’t seem to be any rea-son to do pH probe testing on poorlycontrolled asthmatics, because even if theyare positive, it doesn’t predict who will re-spond to PPI treatment.” ■

Dr. Susan Harding, FCCP, comments: Thisimportant study verifies the findings foundin a previously reported double-blind,placebo-controlled trial examining the effectof esomeprazole 40 mg twice a day for 16weeks in 770 subjects, on asthma outcomes(Kiljander et al. Am. J. Respir. Crit. CareMed. 2006;173:1091-7). Subjects withoutGER symptoms or nighttime asthmasymptoms had no improvement in PEF.Improvement in PEF was noted in subjectswith GER symptoms and nighttime asthmasymptoms. This study verifies that treatmentof asymptomatic acid GER is not indicatedin asthmatics.

THE NUMBER OF EPISODES OFDECREASE IN PEAK FLOW WAS1.7/PERSON PER YEAR IN THE

PLACEBO GROUP AND 2.1 IN THEESOMEPRAZOLE GROUP.

AUGUST 2008 • CHEST P H Y S I C I A N PEDIATRIC CHEST MEDICINE 5

B Y B E T S Y B AT E S


H O N O L U L U — Insight into what’s hap-pening at home may help to explain be-havior problems and school absenteeismin children with asthma, according to stud-ies presented at the annual meeting of thePediatric Academic Societies.

Researchers from the University ofRochester (N.Y.) studied sleep-disorderedbreathing in children with asthma in an at-tempt to find possible links to problem be-havior issues that have previously beenreported in this patient population.

The associations were powerful, withserious behavioral problems documentedin twice as many asthmatic children withsleep problems as in those with asthmaalone, reported Maria Fagnano, healthproject coordinator for the department ofpediatrics at the university.

A second and unrelated study exploredschool absenteeism among children withasthma and found that parental chronic dis-ease plays a role in how children’s healthis perceived and in how many school daysthey miss, regardless of asthma severity.

The New York study enrolled 194 inner-city children aged 4-10 years, with physi-cian-diagnosed asthma, who attended aschool-based asthma program.

Parents were administered a 28-itemvalidated questionnaire on behavioral is-sues (the Behavior Problem Index or BPI)and a 22-item validated questionnaire onsleep patterns, the Sleep-Related BreathingDisorder Subscale.

Most of the children were male (56%);African American (66%) or Hispanic(26%); and on Medicaid (73%). Their av-erage age was 8 years. Prior testing had re-vealed that almost one-third of theirparents suffered from depression.

One-third of the children had sleepscores highly predictive of sleep-disorderedbreathing, which can range from snoringto sleep apnea, said Ms. Fagnano. Girls andchildren with high body mass indexes wereat higher relative risk of elevated sleep-disordered breathing scores than were oth-er children with asthma in the study.

Nearly the same percentage—32% ofchildren—scored above a 14 on the Be-havior Problem Index, a range consideredto be indicative of behavior problems se-rious enough that they might warrantprofessional intervention.

Twice as many children with high sleep-disordered breathing scores—48%—earned elevated scores on the BPI than didthose with normal sleep scores, 24%.

Among problem behavior subscales, in-dependent correlations were found be-tween children with elevated sleep-disordered breathing scores and internaliz-ing behavior problems, externalizing be-havior problems, anxious or depressedbehavior, headstrong behavior—and, in aseparate linear regression analysis, hyper-active behavior.

“A large proportion of urban childrenwith asthma have sleep-disorderedbreathing, and poor sleep is indepen-dently associated with behavior prob-lems,” said Ms. Fagnano.

“Screening for sleep-disordered breathingamong high-risk populations might help to

Look Beyond Asthma Symptoms in Assessing Behavioridentify children who could benefit fromfurther interventions,” she said.

The second study examined data from561 parent/child dyads surveyed as part ofthe nationally representative 2003 Na-tional Health Interview Survey, Dr. EllenA. Lipstein reported at the meeting.

All of the children, aged 5-17 years, hadbeen diagnosed with asthma by a physician,and 39% of their parents reported being di-agnosed with a chronic disease such asheart disease, emphysema or asthma, dia-betes, or arthritis.

No difference was seen in inhaler use bychildren of parents with or withoutchronic disease. When researchers con-trolled for other factors, including mea-sures of childhood asthma severity,parents with chronic disease were threetimes less likely to judge their children’shealth as excellent or very good, and theirchildren missed, on average, 1.3 moredays of school during the previous year.

“These findings suggest that parentalchronic disease may lead to increased per-ceptions of child medical vulnerability,”

said Dr. Lipstein of the Harvard MedicalSchool and the Massachusetts GeneralHospital center for child and adolescenthealth policy, both in Boston. “Further-more, the increased absenteeism suggeststhat parents with chronic disease not onlyperceive [greater] child vulnerability, butthey act on these perceptions,” she said.

Dr. Lipstein said clinicians should beaware that symptom management alonemay not “fully address” the reasons forschool absenteeism among children withasthma. ■

6 CRITICAL CARE MEDICINE CHEST P H Y S I C I A N • AUGUST 2008



The physicians, nurses, and other clin-ical staffers at Tacoma (Wash.) Gen-eral Hospital aren’t sweating the new

Joint Commission on Accreditation ofHealthcare Organizations’ requirementson central line–associated bloodstream in-fections that are scheduled to be phased inthroughout 2009.

That’s because they have already imple-mented a central-line protocol that hasbrought their hospital’s infection rate downto virtually zero over the last few years.

“We just had to change our way ofthinking on it. Rather than accepting a cer-tain rate of infections, we adopted the po-sition that they should never happen,”said Dr. James R. Taylor, FCCP, medical di-rector of the adult intensive care unit atTacoma General Hospital and the hospi-tal’s physician champion on reducing cen-tral-line infections.

In 2005, Dr. Taylor began educatingphysicians and nurses in his ICU about abundle of measures for reducing central-line infections that he learned about aspart of the TICU (Transformation of theICU) project, a program from the nation-al health care alliance VHA Inc. The staff

made an effort to follow the protocol witheach central line placed, and success fol-lowed, Dr. Taylor said.

Before implementing the central-lineprotocol, Tacoma General Hospital had aninfection rate of about 1.5-2.0 infectionsper 1,000 central-line days, which was bet-ter than the national benchmark set by theCenters for Disease Control and Preven-tion. Since it implemented the measures in2005, the hospital’s central line–associatedinfection rate has been even lower. Therewere no infections in the adult ICU atTacoma General Hospital for all of 2006and 2007, said Marcia Patrick, R.N., direc-tor of infection prevention and control forMultiCare Health System, which oper-ates Tacoma General Hospital and threeother hospitals in the area.

After seeing so much success in theICU, the hospital generalized the processto the emergency department, the oper-ating rooms, and anywhere else central-line placement was being performed.

The protocol is surprisingly simple, Dr.Taylor said. Its main elements are properhand hygiene, the use of chlorhexidine-based antiseptic for skin preparation, theuse of a sterile drape to cover the whole pa-tient instead of just the area where the lineis being placed, the placement of the line

Central-Line Infections at Zero With New Protocol

in those locations shown to have lower infection rates, and the removal of thecatheter as soon as possible.

The key is to make it easy to follow themeasures and difficult to do things thewrong way, Dr. Taylor said. For example,the hospital decided to remove from itsline carts anything that might contributeto improper line placement, and to includeonly those materials that would aid inproper line placement.

Another element of the hospital’s success

has been empowering nurses to speak up,Dr. Taylor said. Under the protocol, if aphysician breaks sterile technique duringthe line placement, nurses are required tostep in and ask the physician to stop and startover. The hospital also created a checklist fornurses to record that all the proper steps inthe line placement were performed. ■

Dr. Vera De Palo, FCCP, comments: Afocus on improving patient safety throughthe implementation of strategies to reducecatheter-related bloodstream infection isbeing adopted by many health careinstitutions across the country. Projects likethe TICU project of the national health carealliance VHA Inc. and the advocacy andfacilitation of quality initiatives by theInstitute for Health Care Improvement (IHI)have helped to disseminate these strategies.Large quality collaboratives like the KeystoneICU project in Michigan and the statewideRhode Island ICU Collaborative havesimilarly achieved significant reductions incatheter-related bloodstream infection rates.The work of Dr. Taylor and his team atTacoma General Hospital demonstrates thatwith education and a focus on safety andquality, these excellent outcomes can beachieved and maintained over time, makingit safer for our patients.

The central-line protocol is easy to follow,said Marcia Patrick, R.N., and Dr. Taylor.

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AUGUST 2008 • CHEST P H Y S I C I A N CRITICAL CARE MEDICINE 7



The Joint Commission has issued newrequirements for hospitals in an effortto prevent infections from multidrug-

resistant organisms, central line–associatedbloodstream infections, and surgical site infections.

The requirements, which are part of the2009 National Patient Safety Goals forhospitals, include a 1-year phase-in periodwith full implementation by Jan. 1, 2010.

It is critical that hospitals begin address-ing the issue of health care–associated in-fections and try to keep the problem fromworsening, said Dr. Peter Angood, vicepresident and chief patient safety officer forthe Joint Commission. “We’re in a bit of atight spot and we need to work our wayout of it,” he said.

The new infection control requirementsbuild on an existing National Patient Safe-ty Goal on health care–associated in-fections that had previously included onlyrequirements for compliance with handhygiene guidelines and had called on hos-pitals to manage serious infections as sen-tinel events. Those requirements willremain in place along with the new ele-ments of the goal.

“Infection control is high on our priority list overall,” Dr. Angood said.

Under the new 2009 requirements, hos-pitals are being asked to begin preparingto prevent infections resulting from multi-drug-resistant organisms such as methi-cillin-resistant Staphylococcus aureus,Clostridium difficile, vancomycin-resistantenterococci, multidrug-resistant gram-negative bacteria, and other epidemiolog-ically important organisms.

Starting in January 2010, hospitals willneed to conduct periodic risk assessmentsfor acquisition and transmission of multi-drug-resistant organisms, and educate staffand independent providers about preven-tion strategies and their roles. Hospitalsalso will be required to provide educationabout infection control strategies to patients and families who are infected or colonized with multidrug-resistant organisms.

Hospitals will be required to have a sur-veillance program up and running by

Jan. 1, 2010, that is based on the hospital’srisk assessment.

When indicated by the risk assessment,hospitals will need to implement a labo-ratory-based alert system toidentify new patients with mul-tidrug-resistant organisms, andan alert system to identifyreadmitted or transferred pa-tients who have multidrug-re-sistant organisms.

The Joint Commission alsohas put new requirements inplace to prevent central line–as-sociated bloodstream infectionsand surgical site infections.

As part of the requirementsrelated to central line–associ-ated bloodstream infections,hospitals will be expected touse a catheter checklist and astandardized protocol for cen-tral venous catheter insertion and an all-inclusive standardized supply cart or kit forinsertion of central venous catheters. Therequirements also call for the use of stan-dardized protocols for maximum sterilebarrier precautions during insertion of acentral venous catheter and when disin-fecting catheter hubs and injection portsbefore accessing the ports.

As part of its effort to prevent surgicalsite infections, the Joint Commission is re-quiring hospitals to conduct periodic riskassessments, select surgical site infectionmeasures based on evidence, and evaluatethe effectiveness of their prevention ef-forts. Also, hospital staff will need to mea-sure infection rates for the first 30 daysfollowing most procedures and for thefirst year after procedures involving im-plantable devices.

The surgical site infection requirementswere developed to be in line with well-es-tablished guidelines and should help or-ganizations move toward compliance withthose guidelines, Dr. Angood said.

All of the new requirements related tohealth care–associated infections include a1-year phase-in period, with milestones forplanning, development, and testingthroughout 2009. Allowing organizationsto phase in complex requirements over thecourse of a year helps them to performbetter by achieving concrete goals before

Joint Commission Makes Infection Control Priorityfull compliance is expected, Dr. Angoodsaid.

Addressing health care–associated in-fections is a worthy goal, said Dr. Franklin

Michota, director of academicaffairs for the department ofhospital medicine at the Cleve-land Clinic. There is sufficientevidence to show a clinical ben-efit from implementing infec-tion control strategies. “It’s notan experiment to see if thesethings work,” he said.

Hospitals are likely to facesome up-front costs when im-plementing the new require-ments, Dr. Michota said,especially if they need to put anew educational process inplace to prepare staff. For thatreason, hospitals may be look-ing to involve hospitalists, who

are already on the payroll, in a variety ofactivities related to preventing healthcare–associated infections, he said.

Hospitalists may be involved in devel-oping process improvement plans, trackingrequirements, or tracking infections. Thosewho are not involved on the quality sidemay be asked to champion changes at thefloor level by modeling appropriate hand

hygiene or compliance with contact pre-cautions.

The Joint Commission also has addednew requirements to the goal for med-ication reconciliation. Hospitals are ad-vised to provide a complete andreconciled list of the patient’s medicationsdirectly to the patient and explain the listat the time of discharge. In those settingswhere medications were used minimallyor for a short duration, such as the emer-gency department, the hospital is requiredto perform a modified medication recon-ciliation process. For example, if a short-term course of an antibiotic is prescribed,the patient should be provided with a listcontaining the medications that the pa-tient will continue using after leaving thehospital.

Also new in 2009 is a requirement toeliminate transfusion errors related to pa-tient misidentification. Before beginninga blood or blood component transfusion,hospital staff must match the patient tothe blood during a two-person bedsideverification process. In cases where twoindividuals are not available for thisprocess, a bar code or other automatedtechnology can be used in place of one ofthe individuals, according to the JointCommission. ■

There is sufficientevidence to show a

clinical benefitfrom implementinginfection control

strategies.DR. MICHOTA

2005200420032002200120001999199819971996199519941993

Steady Growth in Methicillin-ResistantStaphylococcus aureus Cases in U.S. Hospitals

Note: Based on data from the Nationwide Inpatient Sample.Source: Healthcare Cost and Utilization Project

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8 PULMONARY PERSPECTIVES CHEST P H Y S I C I A N • AUGUST 2008

Sarcoidosis has often been associatedwith a possible genetic predisposi-tion. However, the closer one looks,

the association with a genetic predisposi-tion becomes less clear.

To date, the amount of information wehave obtained suggests strongly that sar-coidosis is not caused by a single gene oreven a small family of genes. Like manyconditions, such as asthma, there is prob-ably a large number of different genes thataffect the predisposition and clinical out-come of the disease.

For some time, it has been noted thatsarcoidosis occurs in different frequencieswith different ethnic groups.

Although the original description of thedisease was by Hutchins in England (Shar-ma. Clin Dermatol 2007; 25:232), many of theearly studies were per-formed in the Scandi-navian countries.Among the Scandina-vian investigators wasDr. Sven Lofgren at theKarolinska Institute inStockholm. As thestudies accumulated inScandinavian countries,it became clear that theincidence of sarcoidosiswas higher there thanelsewhere in Europe. There also was an in-creased rate of sarcoidosis noted in women.In a comprehensive study of an area in Swe-den by Hillerdal (Hillerdal et al. Am RevRespir Dis 1984; 30:29), the lifetime risk forsarcoidosis in women was 1.3% and almost1% for men. This rate was confirmed bystudies in other Scandinavian countries (Izu-mi. Sarcoidosis 1992; 9:S105).

However, these high rates may havebeen influenced by the availability of na-tional databases allowing for a more com-plete capture of the population. It also hasbeen observed that the rate of sarcoidosiswill increase by one-third if chest radi-ograph screening for TB is employed inthe country.

In the United States, an increased inci-dence of sarcoidosis in the African-Amer-ican population has been frequently noted.However, the absolute numbers were hard-er to obtain. This is, in part, because of thelack of a central database with a collectionof information on all patients. For exam-ple, several studies of military personnel inthe 1950s and 1960s demonstrated an in-creased incidence of sarcoidosis in AfricanAmericans; these studies were composedof, essentially, an all-male population.

Other studies have used death certificatesto verify the increased incidence of sar-coidosis in African-Americans; however,most patients with sarcoid did not die fromsarcoidosis, and death certificates often will not report past medical problems.

The most comprehensive study looking atsarcoidosis in African-Americans vs Cau-casians was from the Henry Ford HealthcareSystem (Rybicki et al. Am J Epidemiol 1997;145:234). This 5-year study demonstratedan increased frequency in African-Americanwomen (lifetime risk, 2.7%) and men (life-time risk, 2.1%) vs Caucasian women (life-time risk, 1.0%) and men (lifetime risk, 0.7%).However, this study required enrollmentinto a health maintenance organization by atleast one family member. Others have re-ported an increased frequency of sarcoido-sis in people without access to medicalinsurance. Therefore, the frequency of thedisease may be even higher.

Familial sarcoidosis also has supported ge-netic predisposition. The reported rate of fa-milial sarcoidosis is around 5%; however, this

is influenced by the un-derlying factor of race.Higher rates of familialsarcoidosis have beenreported in Scandina-vian, Irish, and African-American populations.Studies of families withsarcoidosis have beenused to identify candi-date genes for possible sarcoidosis.These candidate genes

are then tested in the more divergent popu-lation of spontaneous sarcoidosis.

There is compelling evidence to suggestthat sarcoidosis is initiated by the presen-tation of an antigen to the CD-4 T cell,and the resulting complex leads to a Th-1response. The antigen-presenting cell (ei-ther a macrophage or dendritic cell) pre-sents the antigen by the human leukocyteantigen (HLA). There is a large number ofgenes influencing HLA, so studies of theHLA have been an area of focus for can-didate genes in sarcoidosis.

Early studies focused on the HLA class Iantigens. It was found by several investigatorsthat HLA-B8 was associated with acute sar-coidosis. This association alone did not ex-plain most cases of sarcoidosis. Recent studieshave suggested an interaction between classI and class II genes, which may be more im-portant than the class I antigen alone.

Studies of HLA class II antigens have foundseveral interesting associations (Sato et al. AmJ Respir Cell Mol Biol 2002; 27:406; Grunewaldet al. Am J Respir Crit Care Med 2007; 175:40;Maliarik et al. Am J Respir Crit Care Med 1998;158:111). One of the largest studies was per-formed on patients who participated in theACCESS (A Case-Control Etiologic Study ofSarcoidosis) study (Rossman et al. Am J HumGenet 2003; 73:720). The study enrolled pa-tients with newly diagnosed sarcoidosis at 10 centers in the United States. The overallmakeup of study subjects was halfAfrican-American and half Caucasian. The

investigators confirmed an increased suscep-tibility for sarcoidosis in subjects withDRB1*1101 for all patients with sarcoidosis.On the other hand, DRB1*04 was associatedwith possible protection from sarcoidosis,because it was more frequently found in con-trol subjects than patients with sarcoidosis.

Other genes have been associated withan increased risk for sarcoidosis. In a de-tailed gene mapping of 63 German fami-lies with sarcoidosis, Schurmann et al (AmJ Respir Crit Care Med 2000; 162:861) foundpolymorphisms of the butyrophilin-like 2(BTNL2) gene. Studies of American pa-tients by Rybicki et al (Am J Epideiol 1997;145:234) found that BTNL2 was moder-ately associated with sarcoidosis (odds ra-tio of 1.6 for heterozygous and 2.8 forhomozygous). The association was weak-er for African-Americans. The BTNL2 pro-tein is one of a family of genes located inthe major histocompatibility complex classII region. Therefore, it is not clear whetherBTNL2 is an important gene itself or sim-ply located near an important gene. Fur-ther studies on the linkage will be neededto clarify the role of BTNL2.

The prognosis of sarcoidosis also hasbeen found to be influenced by underlyinggenetic factors. Here, the information issomewhat incomplete because of a lack ofa standardized clinical phenotype for pa-tients with sarcoidosis. For example, it isnot clear whether a patient with no evi-dence of active sarcoidosis, but who stillhas residual scarring, should be consideredthe same as a patient with no evidence ofresidual disease. Also, current use of cor-ticosteroid therapy in low doses to main-tain a remission of disease may influencethe clinical outcome of the patient.

For many investigators, one major ex-ception has been Lofgren syndrome. Thepresentation of erythema nodosum, peri-articular arthritis, and hilar adenopathyhas been highly associated with sarcoido-sis. It also has been associated with an ex-cellent clinical outcome. Around 80 to90% of patients with Lofgren syndromewill have complete resolution on chest ra-diograph and resolution of other mani-festations of the disease within a year ortwo. However, there are some patientswith Lofgren syndrome who developchronic disease that lasts beyond 2 years.

Previously, it has been found that theHLA class II genes DQB1*0201 andDRB1*03010 were associated with Lofgrensyndrome for various ethnic groups. Sub-sequently, Grunewald and Eklund (Am JRespir Crit Care Med 2007; 175:40) estab-lished the clinical outcome of patients pre-senting with hilar adenopathy andperiarticular arthritis and/or erythema no-dosum. They determined that men weremore likely to present with arthritis alone,while women were more likely to have ery-thema nodosum. However, the clinicaloutcome for men and women was thesame. They found that while some of theirpatients did quite well, they also found a

group of patients who had chronic disease.They found that 70% of their study popu-lation was DQB1*0201/DRB1*0301-posi-tive and 103 of the 104 patients hadresolution within 2 years. Forty patientswere DQB1*0201/DRB1*0301-negative,and only 22 cases resolved within 2 years.This supports the idea of performing HLAphenotyping to determine patient prog-nosis. While this appears to be quite use-ful in Swedish patients, there is incompleteinformation about its applicability in other populations.

On the other end of the extreme are pa-tients with chronic disease. HLA-DRB3*0101 has been associated withchronic disease in the Caucasian popula-tion. Several groups have noted that theHLA-DRb1*15-positive patients are morelikely to have chronic disease. Dr. Drent’sgroup (Voorter et al. Hum Immunol 2005;66:826) found that, in a Dutch population,DQB1*0602/DRB1*150101 was associatedwith chronic disease and fibrotic changeson chest radiograph.

Another way to look for genetic effecton disease outcome is to examine familialsarcoidosis. In a detailed study of 203African-American families with two ormore members with sarcoidosis, evalua-tion was performed on 509 patients withsarcoidosis. Judson et al (Chest 2006;130:855) reported a similarity between dif-ferent family members and different man-ifestations of the disease. Patients werelikely to share eye and skin problems morefrequently than the population with spon-taneous sarcoidosis.

Interestingly, many of the manifesta-tions of sarcoidosis were not concordantwith the familial cases. Clinical outcomealso was likely to be different betweenfamily members. This lack of close asso-ciation suggests that it is not just geneticsor a single gene that influences the mani-festations of sarcoidosis, at least in theAfrican-American population.

For sarcoidosis, the genetic backgroundseems to be only part of the story. Envi-ronmental exposures also appear to bequite important. It is not clear if there isone or more than one environmentalagent. Several recent reports have associ-ated sarcoidosis with the World TradeCenter disaster, Propionibacter acnes, andmycobacteria (Izbicki et al. Chest 2007;131:1414; Eishi et al. J Clin Microbiol 2002;40:198; Song at al. J Exp Med 2005;201:755). Future research will need tocombine these factors together as we tryto unravel the enigma of sarcoidosis. ■

Dr. Robert P. Baughman, FCCPProfessor of Medicine

University of Cincinnati Medical CenterCincinnati, OH

FOR SARCOIDOSIS, THE GENETIC BACKGROUNDSEEMS TO BE ONLY PART

OF THE STORY.ENVIRONMENTAL EXPOSURES

ALSO APPEAR TO BE QUITE IMPORTANT.

Dr. Gene L. Colice, FCCPEditor, Pulmonary Perspectives

The Role of Genetics in SarcoidosisLike many conditions, there is probably a large number

of genes that affect the outcome of the disease.

SCIENCE OF THORACIC SURGERY

20TH ANNIVERSARY COURSE

Meeting: October 3-4, 2008, Taj Hotel, Boston MA

For more information, contact: David J. Sugarbaker. M.D.,

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10 CHEST P H Y S I C I A N • AUGUST 2008

N E W S F R O M T H E C O L L E G E

B Y E D D E L L E R T, R N, M B A

Vice President, Educational Resources, ACCP

ACCP members expect us to offerquality continuing medical educa-tion (CME) and may take for grant-

ed our ability to provide it. As a clinicaland educational society, members oftenassume that CME occurs automaticallywith many ACCP meetings and products,but have you really thought about whatCME means and the value you placeupon it? Is it really about medical educa-tion, or do you value CME just to get thehours to fulfill your requirements for yourmedical license, your hospital privileges,or your maintenance of certification?

A recent article (J Contin Educ Health Prof2008; 28:95) concluded the following aboutCME and those who participate in it:1. State medical boards should requirevalid and reliable assessment of physi-cians’ learning needs.2. CME planners should create learning

activities on the basis of the assessedpractice needs of physicians.3. CME planners and policy makersshould raise research in CME and physi-cian assessment to a national priority.

In addition to questioning the goals andnature of CME, there are recurring ques-tions about the impact of pharmaceuticalindustry support and potential conflicts ofinterest of physician faculty and partici-pants. There are ongoing discussions bygovernment and professional regulatoryagencies about the role and nature of in-dustry funding of medical education atthe undergraduate and postgraduate lev-els and the safeguards that are in place, aswell as the need to avoid improper influ-ence on content. A number of proposalsand recommendations has come fromvarious quarters. The US Senate FinanceCommittee recommended that policymakers and regulators change their moni-toring system. The American Medical As-sociation’s (AMA) Council on Ethics and

How Much Value Do You REALLY Place on Your CME?Judicial Affairs (CEJA) and the MacyFoundation recommended eliminationof all commercial support in CME.The Association of American MedicalColleges has proposed and received ap-proval to put stricter policies in placeby July 2009 that manage commercialsupport within medical education andconflict of interest of faculty. Thus far,the AMA’s CEJA report was referredback to the committee for furtherstudy. However, the AccreditationCouncil for Continuing Medical Edu-cation (ACCME) has recently imple-mented new policy changes withanother proposal of additional policiesopen for public comment until August11, 2008.

For more information about any orall of these recommendations andproposals, I encourage you to visitthe following Web sites:� US Senate Finance Committeehttp://hcrenewal.blogspot.com/2007/05/senate-finance-committee-report-on.html� Josiah Macy, Jr. Foundation Reportwww.josiahmacyfoundation.org/� AAMC, www.aamc.org/research/coi/� AMA/CEJA, www.policymed.com/2008/06/ama-ceja----bac.html� ACCME, www.accme.org/index.cfm/fa/news.detail/News/.cfm/news_id/c7b2d7ee-854d-4440-9b87-265746af2495.cfm

What can you as an ACCP memberdo in response? First, I suggest that you

consider the value that ACCP educa-tion has in your professional activities,and demand that we provide the high-est-quality CME programs and supportthem. Starting at CHEST 2007, wehave enhanced value by specifying andenriching the learning categories in allof our activities. Applying these learn-ing categories to each ACCP CME cer-tificate reflects the diversity andeffectiveness of learning, along withthe hours in which you participated inACCP medical education programs.

We have responded to your clinicalneeds by offering areas of study thatyou asked for, provided direct and per-sonal feedback to participants in ACCPsimulation center activities, and, also,placed firewalls to manage commercialsupport. All of these efforts meet andexceed the requirements of ACCME.

Education is at the core of theACCP mission, and, perhaps, the mostimportant aspect of our value to ourmembers. Therefore, the ACCP mustnot resist the coming changes in med-ical education; rather, we must em-brace them and lead. With theleadership and support of the College,I believe that others will look to ACCPas the thought leaders who createdvalue that physician learners respectand use in their daily clinical practices.

I welcome your responses, and inviteyou to send them to me at [email protected], so I can share themwith the ACCP Education Committeeand the leadership of the College. ■

The CHEST Foundation’s Makinga Difference Awards Dinner

Saturday, October 25, 2008The CHEST Foundation’s 10th Annu-al Making a Difference Awards Din-ner will honor ACCP members fortheir award winning pro bono serviceprojects from around the world.

There will also be special tribute toForrest M. Bird, MD, PhD,ScD. Dr. Bird is the inven-tor of the world’s firstmass-produced medicalrespirator and the “BABY-Bird,” which significantlyreduced breathing-relatedinfant mortality rates.

Additionally, the ACCPIndustry Advisory Council will confertheir annual award to this year’sCommunity Outreach Event elemen-tary school.

Please join your ACCP colleaguesand friends on Saturday, October 25,2008, at the Philadelphia MarriottDowntown, 1201 Market Street,Philadelphia, PA, for an open recep-tion from 7:00 PM to 7:45 PM, and the

dinner and ceremonies from 8:00 PM

to 10:30 PM.Due to the close proximity of

the Philadelphia Marriott Down-town hotel to other CHEST meetinghotels, transportation will not be provided this year.

The CHEST Founda-tion’s 10th Annual Makinga Difference Awards Dinner Sponsors, to date,are: AstraZeneca, LP;Boehringer IngelheimPharmaceuticals, Inc.; andMerck & Co., Inc.

Making a Difference Society members at the $1,000 levelare entitled to two complimentarytickets. Annual donors at the $500level are entitled to one complimenta-ry ticket.

To register online, go towww.chestfoundation.org. To obtainmore information, contact Teri Ruizat [email protected], or by phone at(847) 498-8308. ■

EDUCATION INSIGHTS

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AUGUST 2008 • CHEST P H Y S I C I A N 11

N E W S F R O M T H E C O L L E G EPRESIDENT’S REPORT

Theeighth

edition ofAntithrom-botic andThrom-bolyticTherapy:

ACCP Evidence-Based ClinicalPractice Guidelines was released inJune (CHEST 2008; 133[suppl]:67S-968S). Over the years, it has provento be the gold standard, evidence-based clinical practice guidelines onthe topic. This publication is 968pages long and weighs 2.5 pounds! Icongratulate the editors, writingpanel, and the ACCP Health andScience Policy Committee that con-tributed to this essential and monu-mental effort. Also, believe it or not,planning for the 9th edition of theguidelines is well underway!

The guidelines have become evenmore important because preven-tion of deep vein thrombosis hasbecome a national (United States)quality indicator for hospitals.

Two important chapters in thesupplement are the guidelines ontreatment and prevention of ve-nous thromboembolism (VTE). Iattended the First Annual Canadi-an Respiratory Conference in Mon-treal ( June 19-21, 2008) and wasmoderator of a presentation on theACCP guidelines for managementand prevention of VTE, given byone of the guideline authors—Dr.William H. Geerts, FCCP. Dr.Geerts gave a wonderful summaryof the management and preventionguidelines. He listed some keychanges in the VTE managementguidelines since the last guidelinesin 2004. They are as follows:� The management guidelines forDVT and pulmonary embolism(PE) are virtually the same;� The addition of fondaparinuxand fixed-dose unmonitored sub-cutaneous heparin (unfractionatedheparin) as acute treatment;� For PE, subcutaneous, low-molec-ular-weight heparin is recommended

ACCP Guidelines Not To Be Missedover IV heparin for nonmassive PE;� There is now more positive considera-tion of catheter-directed thrombus re-duction for DVT and PE;� The guidelines recommend against inferior vena cava filter use unless

anticoagulation is contraindicated; and� There are stronger recommendationsfor indefinite anticoagulation in unpro-voked VTE.

Though some of the above changes arequite interesting and may be controversial,

the evidence clearly supports the recom-mendations. I hope you find the 8th edition of these guidelines to be thought-provoking and an essential guide to theprevention and treatment of these mostimportant and vexing conditions. ■BY DR. ALVIN V.

THOMAS, JR., FCCP

PCCU Lessonsfor August

Management of the Patient WithTraumatic Brain Injury

By Dr. David P. Ciceri

Microangiopathic HemolyticAnemia in the Critically Ill:

Thrombotic ThrombocytopenicPurpura-Hemolytic Uremic

SyndromeBy Dr. Alan Lichtin

October 25 - 30, 2008Philadelphia, PA

Early registration discounts are available through August 29.

Don’t miss these new meeting features at CHEST 2008:

ACCP Clinical Case Puzzlers. Hear master clinicians, pathologists, and radiologists present diagnostic strategies for pulmonary conditions.

Original investigation abstracts and case reports. Use the new digital distribution to easily access the studies before, during, and after CHEST 2008. All attendees also receivethe abstracts on CD.

CHEST 2008 summary CD. Take home valuable information presented during CHEST 2008.

Plus…more of what you like:Sixteen literature review sessions will offer more opportunity to review recently published science.Two unopposed poster grand round presentations will double the time available to view original science.

Additional opportunities in the ACCP Self-study Library will allow you to earn additional CME credit.

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During the blistering summer of 1776, 56courageous men gathered at the PennsylvaniaState House to declare independence fromEngland. Eleven years later, representativesfrom 12 states gathered to shape the USConstitution, finally creating one unifiednation. It all happened in Philadelphia.

Known as the birthplace of our na-tion, Philadelphia is a mecca forUS history. Here, you can retrace

the steps of Benjamin Franklin, catch aglimpse of the Liberty Bell, or tour aformer stop on the Underground Rail-road. These and other celebrated land-marks will give you a brief butfascinating history lesson, sharing howour nation’s past shaped its future.

Step back in time to see, hear, andexperience the early years of the Unit-ed States of America by visiting the fol-lowing sites:� Independence Hall: Located in Inde-pendence National Historic Park, Inde-pendence Hall is the birthplace of boththe Declaration of Independence and

the Constitution. Initially known as thePennsylvania State House, Indepen-dence Hall also is the site where GeorgeWashington was appointed commanderin chief of the Continental Army andwhere the American flag was adopted.� Liberty Bell: Internationally knownsymbol of freedom, the Liberty Bell islocated just steps away from Indepen-dence Hall. Cast in London in 1753,the bell cracked upon its first use. Thebell was recast twice but cracked oncemore in 1846 after it rang for a GeorgeWashington birthday celebration. It hasnot been rung since.� Congress Hall: Home of the USCongress from 1790 to 1800, CongressHall showcases the House of Represen-tatives on the first floor (Lower House)and the recently restored US Senate onthe second floor. � Christ Church and Burial Ground:Christ Church (Protestant Episcopal)was established in 1695, but the currentbuilding dates to 1744. George Wash-ington and John Adams attended

services here, while Benjamin and Deb-orah Franklin and Betsy Ross wereparishioners. Located three blocksfrom the church is the historical burialground, the final resting place for someof the most prominent US leaders, in-cluding Benjamin Franklin and fourother signers of the Declaration of In-dependence. � Franklin Court: Franklin Court isthe site of Benjamin Franklin’s house.The grounds feature a “ghost house,” askeletal structure outlining the shapeand dimensions of Franklin’s home.Also on the grounds is Franklin’s PrintShop, a replica of the 18th centuryprint shop and printing press used byBenjamin Franklin to print the Pennsyl-vania Gazette, the most successfulnewspaper of its time.

Join us at CHEST 2008 in Philadel-phia, the place where history was made.Learn more about Philadelphia’s historyat www.PhiladelphiaUSA.travel/accp.Learn more about CHEST 2008 at www.chestnet.org. ■

Philadelphia—Where History Was Made

October 25-30, 2008

DATES TO KNOWRegistrationAugust 29: Early registration discount ends October 7: Last day for registration refunds(Refunds are not available for simulation registrations or guest fees.)October 8-23: Online registration onlyOctober 24-30: On-site registration available

Housing September 26: Attendee reservation cutoff September 5: Exhibitor reservation cutoff

Guest ToursOctober 9: Preregistration closes


N E W S F R O M T H E C O L L E G ECRITICAL CARE COMMENTARY

Over the last decade, ICUs with in-tensivists (defined as “individualstrained in the subspecialty of criti-

cal care, regardless of their primarytraining”) and other professionals skilledin the delivery of critical care serviceshave received considerable attention.

This attention is the result of multipleforces that vary across institutions butinclude the following goals: (1) improv-ing the quality of care delivered; (2) opti-mizing the efficiency with which ICUcare is provided; and (3) using qualityand/or other performance measures inmarketing or contracting for services.

Several studies have suggested thatmortality can be reduced and length of stay shortened when intensivistsprovide care for patients in an ICU(Pronovost et al. JAMA 2002; 288: 2151;and Young et al. Effective Clinical Prac-tice 2000; 6:284).

These studies were seminal in form-ing the Leapfrog Group, a consortiumof large corporations providing health-care benefits to their employees, orga-nizations of health-care purchasers, andliaisons from several governmental or-ganizations, including the Centers forMedicare and Medicaid Services andthe Department of Defense.

The Leapfrog Group promulgated aset of four practices to improve thequality of inpatient care, defined bylow mortality, high safety and high pa-tient satisfaction, and expecting thathigh quality care is also cost-efficient.

One of these practices is theLeapfrog ICU physician staffing (IPS)standard (www.leapfroggroup.org). Tomeet the IPS standard, the ICU must bemanaged by an intensivist, an inten-sivist must be present during daytimehours, and must provide care exclusive-ly in the ICU. Acknowledging thescarceness and cost of 24/7 physicianstaffing, the Leapfrog IPS standard ac-cepts nonphysician or nonintensivistphysician ICU coverage when they havebeen FCCS-certified (Fundamentals ofCritical Care Support—www.sccm.org)and have intensivist backup readilyavailable during night hours.

Indeed, if the intensivist is not presentor on-site via telemedicine, they mustanswer pages within 5 minutes at least95% of the time and arrange for a physi-cian (or FCCS-certified physician exten-der) to reach the patient within 5minutes (www.leapfroggroup.org/media/file/Leapfrog-ICU PhysicianStaffing Fact Sheet.pdf ).

In the 2006 Leapfrog survey, fewerthan 30% of responding hospitals fullymet the IPS standard. Of the hospitalsnot meeting the IPS standard, cost(61%) and the shortage of intensivists(36%) were cited as moderately to ex-tremely important barriers to meetingthe standard (Pronovost et al. Crit CareMed 2007; 35:2256).

The shortage of intensivists was thefocus of a recent Report to Congressby the Department of Health and Hu-man Services (Health Resources andServices Administration. Report toCongress: The critical care workforce:a study of the supply and demand forcritical care physicians. 2006. SenateReport 108-81). In this extensive analy-sis of critical care manpower, it was es-timated that intensivists cared for lessthan one-third of patients hospitalizedin ICUs in the United States, and that ifthis were increased to only one-half,there would be a shortfall of an addi-tional 25% from the projected availablesupply of criticalcare physicians.

Many centers areexploring the useof telemedicine, es-pecially at night, toincrease the avail-ability of inten-sivist services. While the start-up costscan be high, remotely linked intensivistservices have been shown to improveoutcomes in some settings (Breslow etal. Crit Care Med 2004; 32:31).

The ability to generalize these findings is not yet clear, and the rela-tive merits of this approach as opposedto other staffing methods known alsoare not clear. While intensivists bill forservices rendered, third-party reim-bursement for these services oftendoes not cover their full costs, especially when services are providedat night or when services are mandatedthroughout an ICU whose census orlevel of intensity is variable.

The institutions themselves usuallysubsidize these additional costs. In the2006 Leapfrog survey, over 80% of thehospitals surveyed provided some fi-nancial support for intensivists, and25% of those hospitals meeting the IPSstandard provided full support for in-tensivists (Pronovost et al. Crit CareMed 2007; 35:2256).

In academic centers, house staff cov-erage of ICUs is an option for meetingthe IPS standard. Due to ACGME dutyhour and curricular demands, and a re-duction in the number of house staffin many centers, the supply of avail-able house staff is decreasing while the demand for ICU coverage is in-creasing. Acute Care Nurse Practition-ers (ACNPs) or Physician Assistants(PAs), as physician extenders, can pro-vide first-line ICU care in off-hours at a lower cost than intensivist coverage.In 1997, fewer than 10% of ICUs em-ployed ACNPs or PAs (Brilli et al. CritCare Med 2001; 29: 2007).

Recent reports have examined boththe utility and cost-effectiveness ofACNPs and PAs on the critical caremanagement team (Caserta et al. J Neu-rol Sci 2007; 261:167; and Bloomfield

et al. Mayo Clin Proc 2006; 81: 1457).ACNPs were initially developed withinpediatric programs to extend coveragein the outpatient arena. Their role in in-tensive care was initially within neona-tal ICUs (NICUs), and this experiencepopulates much of the small body ofdata regarding outcomes of care pro-vided by ACNPs. In a controlled trial ofpatient care in a NICU by ACNPs vs pe-diatric residents, when supervised byneonatologists, outcomes (short andlong-term), costs of care, and patientsatisfaction did not differ significantly.Similar results can be obtained in adultsubspecialty ICUs, as well (Caserta et

al. J Neurol Sci 2007;261:167). The MayoClinic, however,found 24/7Leapfrog-compliantcoverage by ACNPs or PAs tobe more expensive

than house staff coverage, but costsvaried widely across the three sitesstudied due to the numbers of avail-able house staff. The cost of house staffdid not take into account the inefficien-cy of house staff rotation and orienta-tion to the ICUs or the costs related tothe role of attending physicians in theeducational program of house staff,but neither did it account for Medicaredirect and indirect medical educationreimbursements.

A recent study examined the impactof providing 24/7 continuous, ratherthan on-demand, attending coverage ina single medical ICU that was staffedby residents and fellows at all times(Gajic et al. Crit Care Med 2008; 36:36).Continuous, rather than on-demand at-tending coverage, was associated witha small, statistically insignificant reduc-tion in readmission to the ICU, withimproved patient satisfaction and amodest increase in adherence to rec-ommended processes of care (to whichthere was already very high adher-ence). There were no changes seen inlength of stay or mortality. The mar-ginal benefit of continuous intensivistcoverage requires additional study indifferent settings and with variousmodels of care.

A plan for optimizing ICU staffingshould also take into account the levelof experience of the nursing and ancil-lary staff during day and night shifts.Studies cited by the Agency for Healthcare Research and Quality(www.ahrq.gov) demonstrate that amore experienced staff, especially atnight, improved patient outcomes andlowered overall costs of care. Having a more experienced staff during offhours, however, increases the ICU’sbudget for salaries.

Each facility and their specific needsshould dictate the model for care

teams and integration of house staff,attending physicians, and ACNPs/PAs.In situations where house staff is eithernot available or not present in suffi-cient numbers to provide coverage,ACNPs or PAs appear to provide an ac-ceptable and cost-effective staffingmodel. House staff and ACNP/PAstaffing models are not mutually exclu-sive, and both can be integrated intomodels that provide 24/7 bedside cov-erage for critically ill patients. Indeed,ACNPs/PAs assigned to specific ICUswould likely adhere more strictly toguidelines and recommended practicesthan house staff who rotate acrossmultiple hospital services.

Areas that require discussion and res-olution of potential conflict include thefollowing: (1) the institutional commit-ment (both administrative, financial,and cultural) to the ACNP/PA pro-gram; (2) implementation of a compre-hensive program with a definedACNP/PA coordinator (rather thanhiring a single practitioner); and (3) orientation and education for attendingstaff, house staff, bedside nurses, andACNPs/PAs that stresses the comple-mentary roles of house staff and ACNPs/PAs and a team-based ap-proach to care ( Jastremski. SeminRespir Crit Care Med 2001; 22:89).

Recently, Levy and colleagues (AnnIntern Med 2008; 148;801) reported thatintensivist care resulted in increasedcosts and mortality. However, the levelof intensivist involvement (consulta-tion, co-management, full manage-ment) and intensivist presence in theICU and responsibility for unit man-agement (all components of theLeapfrog IPS) were not reported.

While the bulk of evidence indi-cates that high intensity staffing (eg,Leapfrog IPS) is associated with im-proved outcomes and lower globalcosts, studies examining the impact on cost and quality of care of thesediffering practice models are urgentlyneeded.

Until the various practice permuta-tions have been comprehensively analyzed, development of an optimal,institution-specific staffing model remains as much an art as it is a science. ■

Dr. David L. Bowton, FCCP, FCCMProfessor and Head, Section on Critical Care

Department of AnesthesiologyWake Forest University School of Medicine

Winston Salem, NC

Dr. Peter Spiro, FCCPAssistant Professor of Clinical Medicine

Columbia University College of Physicians and Surgeons

Head, MICUHarlem Hospital Center

New York, NY

ICU Staffing: What Is the Optimal Mix of Providers?

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N E W S F R O M T H E C O L L E G ENETWORKS

Updates on New TB Tests, IPFnet, and Sleepy Workers Chest InfectionsRecently, two T-cell based interferon-gam-ma release assays (IGRAs) for the diagno-sis of TB infection have been licensed forcommercial distribution: the QuantiFER-ON® -TB Gold (Cellestis, Victoria, Aus-tralia) and the T-SPOT.TB® (OxfordImmunotec, Oxford, UK). IGRAs haveseveral advantages over the tuberculin skintest (TST), mainly related to ease of testadministration and patient convenience.An additional advantage is that IGRAs donot cross-react with antigens in the BacilleCalmette-Guerin (BCG) vaccine.

How should these new tests be used?The US Centers for Disease Control andPrevention recommends that IGRAs maybe used in place of the TST in “all circum-stances” where the TST is currently beingused, including the evaluation of suspectedTB disease and screening for latent TB in-fection (LTBI). Other groups have issuedmore conservative guidelines. The UK Na-tional Institute for Clinical Excellence has

suggested screening most patients initiallywith the TST and using IGRA as a secondtest if the TST is positive. Both the IGRAand TST may be negative in the setting ofthe individual patient with active TB. Simi-larly, neither the IGRA nor the TST can beused to distinguish active from latent TB.

What is the role of IGRAs for large scalescreening programs? We feel the IGRAmay have a role in screening for LTBI inhealth-care workers, particularly thosewho have received prior BCG vaccination.In July 2007, the Cleveland Clinic begantesting all new employees at our institutionwith IGRA in lieu of the TST. This led to anumber of laboratory and financial chal-lenges related to large-scale implementa-tion of a new test (over 2,000 tests in thefirst 9 months). We also observed an 8%prevalence of indeterminate IGRA resultsthat necessitated additional protocols forweekly tracking of indeterminate results.

A number of questions regarding large-scale IGRA testing remains, including the

reproducibility of T-cell responsesover time and the appropriate thresh-old (cutoff ) to define an IGRA conver-sion. Successful implementation ofIGRA requires education of all stake-holders involved and flexibility, as newstudies evaluate the feasibility and value of these tests.

Dr. Carlos M. Isada, FCCP Steering Committee Member;

and Dr. Steven M. Gordon

Interstitial and Diffuse Lung DiseaseLast year, we reported on the devel-opment of the IPFnet projects spon-sored by the NIH. We would like totake an opportunity to update you onthe progress involved in this very im-portant clinical research effort.

The IPFnet is charged with the devel-opment and implementation of clinicaltrials. The steering committee consistsof 11 centers (University of Chicago,University of California San Francisco,University of California Los Angeles,University of Washington, Weil Cor-nell, Mayo University, University ofMichigan, Vanderbilt University, TulaneUniversity/University of AlabamaBirmingham, Emory University, andNational Jewish Medical Center in Den-ver) and now several additional centers(St. Lukes - St Louis, Cleveland Clinic,University of South Carolina, Universityof Pennsylvania, Highland Hospital-University of Rochester, Duke Universi-ty, University of Miami, Yale University,and University of Utah) are being addedto more comprehensively provide anopportunity for subjects to enroll.

Two trials have been developed, anda third is being designed. The IPFnethopes that these efforts will improve thecare of these difficult-to-treat patients.The IPFnet is currently enrolling sub-jects into the STEP (sildenafil trial ofexercise performance in idiopathic pul-monary fibrosis) with great success. Asits name implies, this study is focusedon improving 6-min walk testing withsildenafil. The implications for an im-proved quality of life in patients with se-vere disease are clear. This category ofpatients has not been and will likely notbe involved in pharmaceutical trials.

The Panther protocol, looking atprednisone, azathioprine and N-acetyl-cysteine, is fully approved and awaitingcompletion of study drug production.The IPFnet hopes to answer the ques-tion once and for all regarding the mer-its of what has been described as the“standard of care” with this placebo-controlled trial. This critical questioncan only be answered with enthusiasticenrollment on everyone’s part.

The IPFnet is developing a thirdprotocol with more details to come.We hope that pulmonary practition-ers will take advantage of the IPFnet

and the protocols to offer treatmentoptions to these patients. Only withenrollment in such efforts will effec-tive therapies be found.

Dr. Imre Noth, FCCP, NetWork Vice-Chair

Sleep MedicineAs part of its 11th annual Sleep Aware-ness Week, the National Sleep Founda-tion published its “Sleep in America”poll in March 2008. (Read about the results of the ACCP’s “ECHO” Poll on page 19 of the May 2008 CHESTPhysician at www.chestnet.org/physician/0508.pdf.)

One thousand Americans, age 18years and older and working at least30 hours per week, were interviewedby telephone for this year’s poll,which focused on American workers.

Those surveyed work, on average,nearly 45 hours weekly. Workdays aver-age 9 hours and 28 minutes, and 13% ofthe respondents work greater than orequal to 60 hours weekly. Americanworkers, on average, sleep only 6 hoursand 40 minutes on workdays. On non-workdays, they sleep about 7 hours and25 minutes. One in six sleeps less than 6hours nightly.

Nearly half awaken not refreshed atleast a few days each month. In > 40%,sleep problems occur nightly or almostnightly, and 5% never get a good night’ssleep! Nearly half of the respondentsnap at least twice per month, for nearly1 hour per nap; 10% of workers havenapped at work. Of those interviewed,32% reported that they drove whiledrowsy at least once a month in the pastyear, while 36% of drivers have noddedoff or fallen asleep while driving.

Eleven percent report difficulty infalling asleep, staying asleep, waking uptoo early, and that sleepiness interfereswith their daytime functioning. Sixtypercent of those with insomnia drivedrowsy! Similar impairments were ex-perienced among the 11% found to sat-isfy clinical criteria for restless legssyndrome (RLS) and the 14% at risk forobstructive sleep apnea (OSA).

Despite meeting clinical criteria forinsomnia, OSA, or RLS, respondentsare underdiagnosed by their physi-cians. While 14% meet criteria for be-ing at risk for OSA, only 9% havebeen diagnosed, and only about one-third are being treated.

Modern economic pressures andmodern technology have caused theworkplace to encroach more on freetime at the expense of sleep. Poorsleep, short sleep, and long hours con-tribute to multiple effects on the qual-ity of work, including injuries tothemselves or others at work.

Dr. Steven M. Brown, FCCP NetWork Member



��IDr. Mary Anne McCaffree, FCCP,has been elected to the AMA Boardof Trustees.

Currently, Dr. McCaffree is thechair of the Council on Science andPublic Health, a prominent advisorycommittee to the AMA, and a mem-ber of the Pediatric Section Councilof the AMA. Dr. McCaffree is a pro-fessor of pediatrics at the Universityof Oklahoma Health Sciences Centerin Oklahoma City, and she is recog-nized as an experienced researcherand leader.

She is committed to ensuring thatall patients receive quality health careand previously led the state of Okla-homa to expand care for sick new-borns, working within the medicalcommunity groups to implementchanges to improve care for infantsand children. Dr. McCaffree chairedthe ACCP Women’s Health Networkand is actively involved in the outreachprograms for school children, focusingon prevention of tobacco use. � Dr. Richard S. Irwin, FCCP, andCynthia French, NP, MS, have beenawarded the MDA Lou Gehrig

Humanitarian Award by the MuscularDystrophy Association for their workproviding interdisciplinary and pa-tient-focused care for more than 25years to people with amyotrophic lat-eral sclerosis (ALS).

Dr. Irwin and Ms. French, who be-gan treating patients with ALS forpulmonary-related complications inthe Lung and Allergy Center atUMass Memorial Medical Center al-most 25 years ago, noticed that mostof their patients had difficulty manag-ing appointments with multiple doc-tors at multiple locations. Theyworked to foster an interdisciplinaryapproach to treatment with servicescentralized in one location.

The award was presented to Irwinand French by Dr. David Chad, direc-tor of the MDA/ALS Center atUMass Memorial Medical Center, andwinner of last year's MDA LouGehrig Humanitarian Award. Dr. Ir-win is the Editor in Chief of the jour-nal CHEST, and Ms. French is theAssistant Editor.

The ACCP congratulates you onthese great achievements! ■

ACCP CongratulatesThree for Achievements

B Y D R . R I C H A R D S.

I R W I N, F C C P

Editor in Chief, CHEST

� Long-term Use of Sildenafil inInoperable Chronic ThromboembolicPulmonary Hypertension.By Dr. J. Suntharalingam, et al.

� Comparison of a Combination ofTiotropium Plus Formoterol toSalmeterol Plus Fluticasone inModerate COPD.By Dr. K. F. Rabe, et al.

� Predictors of 30-Day Mortality andHospital Costs in Patients WithVentilator-Associated PneumoniaAttributed to Potentially Antibiotic-Resistant Gram-Negative Bacteria.By Dr. K. E. Kollef, et al.

� Impact of Cough Across DifferentChronic Respiratory Diseases:Comparison of Two Cough-Specific,

Health-Related Quality of LifeQuestionnaires.By Dr. L. Polley, et al.

� Role of the Ethics Committee:Helping To Address Value Conflictsor Uncertainties.By Dr. M. P. Aulisio, and Dr. R. M. Arnold

� Illnesses at High Altitude.By Dr. R. B. Schoene

www.chestjournal.org

This Month in CHEST:Editor’s Picks

Journal Citation Report: CHEST Impact Factor Increases In June, the Journal Citation Report

statistics (including impact factor)for 2007 were released by the Insti-tute of Scientific Information (ISI).CHEST fared well, with its impact fac-tor rising from 3.924 to 4.143—itshighest impact factor ever. CHEST'simpact factor ranking remains 6thout of 34 respiratory journals.

CHEST also scored highly in the

following Journal Citation Report cat-egories:� Total Citations: 35,675 (ranked 2ndof 34 journals)� Number of Articles: 560 (ranked2nd of 34 journals)� Immediacy Index: 0.918 (ranked5th of 34 journals)� Cited Half-Life: 7.0 (ranked 10th of34 journals) ■

ACCP Critical Care Board Review Course 2008

August 22 - 26

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ACCP Pulmonary Board Review Course 2008

August 27 – 31


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16 CARDIOTHORACIC SURGERY CHEST P H Y S I C I A N • AUGUST 2008

Proposed Staging System Aids Lung Cancer PatientsB Y D O U G B R U N K


S A N D I E G O — Application of a stagingsystem proposed by the International As-sociation for the Study of Lung Cancer re-sulted in a statistically significant interstageshift in 17% of patients, results from alarge single-center study demonstrated.

In addition, the stage shift may alter dis-ease management in 12% of patients, Dr.Edmund S. Kassis reported at the annualmeeting of the American Association forThoracic Surgery.

“We conclude that the IASLC system ismore effective than the UICC-6 [Union Internationale Contre le Cancer–sixth edi-tion] at differentiating operable patientsbased on stage,” said Dr. Kassis of the de-partment of thoracic and cardiovascularsurgery at the University of Texas M.D.Anderson Cancer Center, Houston.

“Use of this system will help to identi-fy those patients at higher risk for recur-rence and will facilitate adjuvant treatmentdecisions and research,” he said.

Adopted in 1997, the UICC-6 stagingsystem has remained unrevised despiteadvances in imaging and statisticalmethodology. The IASLC staging com-mittee recently proposed changes to the

T, M, and overall stage groupings. Thecommittee’s proposal was recently sub-mitted to the UICC and a decision is ex-pected to be rendered in 2009.

The proposed changes to the overallstage groupings could lead to stagechanges that might alter treatment, Dr.Kassis said. These include node negativetumors greater than 5 cm ( J. Thorac. On-col. 2007;2:593-602). “This will change thestage from IB where surgery alone is thecurrent treatment to IIA or IIB where ad-juvant therapy is frequently recommend-ed,” he explained. “Also, tumors greaterthan 7 cm with N1 disease will be restagedfrom stage IIB to stage IIIA.”

Primary lobe satellite tumors will be re-classified as IIB or IIIA depending on thepresence or absence of nodal disease.Satellite nodules in nonprimary lobe willalso be reclassified with stage dependingon the presence of nodal disease.

To determine the effects of applying theIASLC staging system on patients’ stageand to directly compare the IASLC andUICC-6 systems’ effectiveness at stratifyingoperable patients, Dr. Kassis and his asso-ciates studied 1,154 patients who under-went complete surgical resection fornon–small cell lung cancer at M.D. Ander-son Cancer Center between 1998 and 2006.

Pre- or postoperative chemotherapy or ra-diation therapy were not exclusion criteria.

Pathologic data for each patient wereentered into a prospectively collected data-base and the T, M, and overall stage group-ings of both the UICC-6 and IASLCsystems were applied to each patient.

The mean age of the patients was 66years and 53% were male. Most patients hadeither adenocarcinoma (57%) or squamouscell disease (34%), and the majority (82%)underwent lobectomy or bilobectomy.

Dr. Kassis reported that application ofthe IASLC system resulted in a statistical-ly significant shift of patients betweenstages, with a total of 202 (17%) patientschanging stage. Of these 202 patients, 73were upstaged and 129 were downstaged.

Of the 73 patients who were upstaged,63 stage IB patients were upstaged to ei-ther stage IIA or IIB, and 10 stage IIB pa-tients were upstaged to IIIA.

Of the 129 patients who were down-staged, 67 IIB patients were downstaged toIIA. Of 59 IIIB patients, 8 were down-staged to IIB and 51 were downstaged toIIIA. Of the three stage IV patients, twowere downstaged to IIIA and one wasdownstaged to IIIB.

Dr. Kassis said the IASLC system poten-tially altered management in 134 (12%) of

patients. No patients were upstaged to anunresectable stage, 63 patients were up-staged to a stage where adjuvantchemotherapy is frequently offered, and 61patients were downstaged from IIIB or IVto a stage often offered surgical resection.

The researchers were concerned thatshifting patients from UICC-6 IIIB/IV intoIASLC IIIA would compromise 5-year sur-vival. However, the 5-year survival forIASLC IIIA and UICC-6 IIIA were compa-rable at 39% and 37%, respectively.

Dr. Kassis had no conflicts of interest. ■

INDEX OFADVERTISERS

Nationwide Medical BillingCorporate 4, 7

Ortho-McNeil-Janssen Pharmaceuticals, Inc.Doribax 19-20

Respironics, Inc.CoughAssist 11

Science of Thoracic Surgery20th Anniversary Course 10

Sepracor Inc.Alvesco 9

UreSil, LLCTru-Close 5

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PROFESSIONAL OPPORTUNITIES

Pulmonary/Critical Care/SleepWest Central Florida group seeks BC/BE tojoin practice encompassing all aspects ofpulmonary, critical care and sleep medi-cine, office and hospital practice. Earlypartnership, competitive salary and fringebenefits. Please respond with CV to Chest#74, P.O. Box 996, Abingdon, MD 21009.

BC/BE PULMONARYCRITICAL CARE

PHOENIX, AZ - BC/BE PULMONARYCRITICAL CARE - Join an established, pro-gressive, pulmonary group with five mem-bers seeking to add a sixth. Partnershipopportunity available for the right candidate.J1 OK. Fax CV to 623.523.6475 or [email protected]

NORTH CAROLINA-NEAR PINEHURSTPULMONOLOGIST

Assume private practice or be employed infamily community located less than twohours from beaches, Charlotte, Raleigh andjust 35 minutes from golf resort of Pinehurst.Contact Melisa Ciarrocca at 800-764-7497,Fax: 910-276-0470 or email:[email protected]: www.scotlandhealth.org

DisclaimerCHEST PHYSICIAN assumes the statements made in classified advertisements are accurate, but can-not investigate the statements and assumes no responsibility or liability concerning their content.The Publisher reserves the right to decline, withdraw, or edit advertisements. Every effort will bemade to avoid mistakes, but responsibility cannot be accepted for clerical or printer errors.

FOR INFORMATION ON CLASSIFIEDS:Contact: Rhonda Beamer, Walchli Tauber Group, Inc., 2225 Old Emmorton Road, Suite 201,Bel Air, MD 21015. (443) 512-8899 Ext 106. FAX: (443) 512-8909.Email ad to: [email protected]

Northern, New JerseyDesirable location within a short drive fromNew York City. Located in the rolling hills ofnorthern New Jersey is a fully renovatedcommunity hospital. Intensivist needed tojoin a successful single specialty practice of-fering partnership in twenty-four months.Submit CV to [email protected] forimmediate consideration.

Suburban PittsburghPulmonary and Sleep Medicine Physicianneeded in suburban Pittsburgh, PA. Excel-lent salary and fringe benefits. Equal Op-portunity Employer. J-1 Visa consideration.Please send CV to Chest #84, P.O. Box 996,Abingdon, MD 21009.

P u l m o n a r y , C r i t i c a l C a r e a n d S l e e p M e d i c i n e

All inquiries will be kept in strict confidence.

I N T E N S I V I S T J O B SA D I V I S I O N O F P H Y S I C I A N T E C H N O L O G I E S

Hospitalist Opportunity

Physician Recruitment800-650-0625916-643-6677 [email protected]

Northern California

Sutter Medical Group is seeking a Hospitalist to join their successful expanding Hospitalist program in Auburn, CA. Candidate must have two years of recent experience doing procedures and be able to handle ICU coverage.

• 2-year shareholder track• Generous compensation• Competitive benefits package• Excellent retirement package• Wide variety of shifts available• School system is one of the best in CA• Great quality of life

Sutter Auburn Faith Hospital, has 95 beds, a 24/7 Hospitalist program, open ICU, high resolution CT scan, cardiac cath lab, full nuclear medicine department, bronchoscopy suites and a pulmonary function laboratory.

The community of Auburn is nestled in the Sierra Nevada Foothills approximately 35 miles northeast of Sacramento. Auburn is known for its family-oriented atmosphere and for its excellent schools. Residents enjoy year-round outdoor recreations such as golfing, hiking, biking, and white water rafting.

Northern CaliforniaPulmonary Critical Care Opportunity

Sutter Medical Group (SMG) is seeking a BE/BC Pulmonary Critical Care physician in Auburn, CA. Good call schedule. Option for hospitalist work if desired.

SMG is a multi-specialty group of over 300+ members. SMG offers an income guarantee with shareholder track, generous compensation, benefits, and retirement package.

Sutter Auburn Faith Hospital is a medium sized hospital with a 24/7 hospitalist program, open ICU, high resolution CT scan, cardiac cath lab, full nuclear medicine depart-ment, bronchoscopy suites and a pulmonary function laboratory.

Auburn is centrally located in the Sierra Nevada foothills between Sacramento and Lake Tahoe. Auburn is close to shopping and restaurants, and offers a variety of outdoor activities.

Physician Recruitment800-650-0625916-643-6677 [email protected]

SCIENCE OF THORACIC SURGERY

20TH ANNIVERSARY COURSE

Meeting: October 3-4, 2008, Taj Hotel, Boston MA

For more information, contact: David J. Sugarbaker. M.D.,

Division of Thoracic Surgery, Brigham and Women’s Hospital,

75 Francis Street, Boston, MA 02115(telephone: 617-732-6824;

Website: Please go to www.cme.hms.harvard.edu/

courses/thoracicsurgery for syllabus

and registration information).

KEEP UP-TO-DATEWatch our Classified Notices

for Post Graduate Course Information

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Severe Sleep Apnea Raised All-Cause Mortality in 14-Year Study

B Y H E I D I S P L E T E


B A LT I M O R E — Moderate to severesleep apnea significantly increased therisk of all-cause mortality, accordingto 14 years of follow-up data from alarge community sample.

“Sleep apnea is a disease of publichealth significance,” said NathanielMarshall, Ph.D., of the University ofSydney, who presented results fromthe Busselton Health Study at the an-nual meeting of the Associated Pro-fessional Sleep Societies.

Previous studies have suggestedthat obstructive sleep apnea (OSA) in-creases the risk of death from cardio-vascular disease, Dr. Marshall said.Until recently, however, the role ofsleep apnea as an independent pre-dictor of all-cause mortality has notbeen well studied, he added.

The Busselton Health Study is anongoing community-based study inBusselton, Western Australia. For thestudy, the researchers analyzed datafrom 400 community-dwelling adultsaged 45-60 years. The participantswere tested for OSA using a homesleep apnea monitoring device. Sleepapnea was quantified using the respi-ratory disturbance index (RDI), andmoderate to severe apnea was definedas an RDI score of 15 or more respi-ratory disruptions per hour of sleep.

Complete data were available from380 participants (278 men and 102women) after an average of 13.4years. The mortality rate was signifi-cantly higher (33.3%) among the 18

participants with moderate to severeapnea (six deaths), compared with6.5% among the 77 participants withmild OSA (five deaths) and 7.7%among the 285 participants withoutOSA (22 deaths).

Compared with people who did nothave sleep apnea, the mortality hazardratio was 6.24 for people with mod-erate to severe sleep apnea, after theresearchers controlled for age, gender,body mass index, mean arterial pres-sure (as a measure of blood pressure),smoking status, total cholesterol,HDL cholesterol, diabetes status, andphysician-diagnosed angina.

“I was suspicious of the size of thiseffect,” Dr. Marshall said. “If you putthis same model into an odds ratio,you get an odds ratio of about10.” To put it another way,“sleep apnea has about thesame effect on mortality asgetting 18 years older,” he said.

But the results reflect simi-lar recent findings from twostudies in the United States—the multicenter Sleep HeartHealth Study and the Wis-consin Sleep Study—that alsoshow significant independentassociations between OSAand all-cause mortality.

The association betweenmoderate to severe OSA andall-cause mortality in the Bus-selton Health Study persistedeven in a partly adjusted model that did not control forblood pressure. That modelwas used for comparison

because OSA is a known cause of hy-pertension, Dr. Marshall noted. How-ever, the researchers found nosignificant association between mildsleep apnea and an increased risk ofdeath, which is good news, he said.

The study was limited by a lack ofinformation about any treatment ofsleep apnea in the study group, butthe community-based format of thestudy kept it free of clinical referralbias, said Dr. Marshall.

The findings emphasize the needfor randomized controlled trials ofsleep apnea treatments that are de-signed to identify reductions in mor-tality risk, Dr. Marshall noted.

Dr. Marshall reported that he hadno financial conflicts to disclose. ■

Apnea May PromoteInsulin Resistance

B A LT I M O R E — Obstructive sleep apnea in chil-dren did not contribute to insulin sensitivity direct-ly, but it was significantly associated with loweradiponectin independent of obesity and puberty ina study of 97 children.

“We hypothesized that obstructive sleep apneasyndrome worsens insulin resistance independent-ly of both obesity and puberty by lowering the adi-pose-derived insulin sensitizer, adiponectin,” notedDr. Andrea Kelly, an endocrinologist who present-ed the results of the study at the annual meeting ofthe Associated Professional Sleep Societies.

Obstructive sleep apnea (OSA) has been linked tometabolic syndrome, but its effect on insulin resistancehas not been well studied in children because it is as-sociated with both obesity and puberty, which are rec-ognized contributors to insulin sensitivity, she said.

In this study, Dr. Kelly and her colleagues at theChildren’s Hospital of Philadelphia collectedpolysomnography data from 97 children aged 4-18years (mean age 10.5 years). The researchers cate-gorized the children as pubertal or prepubertal basedon Tanner stages and obtained data on fasting bloodglucose, insulin, and adiponectin. The children weregenerally overweight (the average BMI z score was2.1) and the average insulin sensitivity based onhomeostatic model assessment was 2.7.

After adjustment for puberty and BMI, none of thepolysomnographic indicators of OSA was signifi-cantly associated with insulin resistance. But threepolysomnographic indicators of OSA—the apnea-hypopnea index, the end-tidal CO2, and the percent-age of time that oxygen saturation was less than90%—were negatively associated with adiponectin.

More research is needed to confirm a causal rela-tionship between OSA and lower adiponectin, but ifsuch a relationship is confirmed, long-term OSA inchildren may contribute to an increased risk of insulinresistance, diabetes, and atherogenesis, Dr. Kelly said.

Dr. Kelly reported that she had no financial con-flicts to disclose.

—Heidi Splete

Higher All-Cause MortalityWith Severe Sleep Apnea

Note: Based on an average 13.4-year follow-up of adults aged 45-60 years.Source: Dr. Marshall

None(n = 285)

Mild(n = 77)

Moderate to severe

(n = 18)

Severity of obstructive sleep apnea

33.3%

6.5% 7.7%E

LS

EV

IER

GL

OB

AL

ME

DIC

AL

NE

WS

18 SLEEP MEDICINE CHEST P H Y S I C I A N • AUGUST 2008

SOUTHERN CALIFORNIAPULMONARY/CRITICAL CARE OPPORTUNITY

Our well-established, dynamic group is looking for BC/BE Pulmonologist/CCM Physicianto join as a future partner to one of the largest, most well respected, successful pulmonarypractices in the Greater Los Angeles and San Gabriel Valley areas. Join an excellent groupof physicians who are life style and family oriented. Live in a great location which offersan abundance of cultural and recreational activities. This busy inpatient/outpatientpractice encompasses all aspects of Pulmonary and Critical Care for great growthopportunities. Offers competitive compensation and excellent benefits leading to early,full partnership. Fax CV to: 626-795-2716 Attn: Tania or email to [email protected]

Marietta Pulmonary MedicineSuburban Atlanta

Well-established, busy eleven-physician single-specialty Pulmonary practice in suburban Atlanta,Georgia, looking for one or more BC/BE Pulmonary/Critical Care physicians. Sleep certifica-tion is a plus. Practice includes all aspects of pulmonary medicine, including critical care, sleepmedicine, out-patient clinic, pulmonary rehab and clinical research. Practice located at two largeacute-care hospitals, with one being the busiest ER in Georgia, and also rounds at a near-bylong term acute care hospital. Competitive salary with bonus potential and generous benefitspackage. Fax CV to: 770-792-1738.

IntensivistNEW YORK – Desirable Coastal Long Is-land Community. Intensivist needed fornew program at state of the art communityhospital. Just a short drive or train ride tometropolitan area. Excellent schools andbeautiful homes. Excellent salary and earn-ing potential and full benefits. Submit CV [email protected]

BEAUTIFUL COAST OF MAINEBC/BE Pulmonologist

Modern, multi-specialty community hospital seeks full-time physician for outpatient prac-tice. Belfast offers beautiful views of Penobscot Bay. Ideal for outdoor enthusiasts. Fam-ily oriented with excellent schools. Immediate availability. Contact Mark Biscone,Executive Director, Waldo County General Hospital, PO Box 287, Belfast, ME 04915, 207-338-9302, E-mail: [email protected] Website: www.wchi.com

Help Fight LeukemiaDonate Bloodand Platelets

For information ondonating blood,

Call 1-800-GIVE-LIFEOr contact your local Red Cross

DORIBAX™(doripenem for injection)for Intravenous Infusion

Brief Summary: The following is a brief summary only. Before prescribing,see complete Prescribing Information in DORIBAXTM (doripenem forinjection) labeling.

To reduce the development of drug-resistant bacteria and maintainthe effectiveness of DORIBAXTM and other antibacterial drugs,DORIBAXTM should be used only to treat infections that are proven orstrongly suspected to be caused by susceptible bacteria. Whenculture and susceptibility information are available, they should beconsidered in selecting and modifying antibacterial therapy. In theabsence of such data, local epidemiology and susceptibility patternsmay contribute to the empiric selection of therapy.

CONTRAINDICATIONSDORIBAXTM is contraindicated in patients with known serioushypersensitivity to doripenem or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to beta-lactams.

WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Serious and occasionally fatalhypersensitivity (anaphylactic) and serious skin reactions have beenreported in patients receiving beta-lactam antibiotics. Thesereactions are more likely to occur in individuals with a history ofsensitivity to multiple allergens. Before therapy with DORIBAXTM isinstituted, careful inquiry should be made to determine whether thepatient has had a previous hypersensitivity reaction to othercarbapenems, cephalosporins, penicillins or other allergens. If thisproduct is to be given to a penicillin- or other beta-lactam-allergicpatient, caution should be exercised because cross-hyperreactivityamong beta-lactam antibiotics has been clearly documented.

If an allergic reaction to DORIBAXTM occurs, discontinue the drug.Serious acute hypersensitivity (anaphylactic) reactions requireemergency treatment with epinephrine and other emergency measures,including oxygen, IV fluids, IV antihistamines, corticosteroids, pressoramines and airway management, as clinically indicated.

Interaction with Sodium Valproate: Carbapenems may reduce serumvalproic acid concentrations to subtherapeutic levels, resulting in lossof seizure control. Serum valproic acid concentrations should bemonitored frequently after initiating carbapenem therapy. Alternativeantibacterial or anticonvulsant therapy should be considered if serumvalproic acid concentrations cannot be maintained in the therapeuticrange or seizures occur. [see Drug Interactions]

Clostridium difficile-Associated Diarrhea: Clostridium difficile -associated diarrhea (CDAD) has been reported with nearly allantibacterial agents and may range in severity from mild diarrhea tofatal colitis.

Treatment with antibacterial agents alters the normal flora of thecolon and may permit overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to thedevelopment of CDAD. Hypertoxin producing strains of C. difficilecause increased morbidity and mortality, as these infections can berefractory to antimicrobial therapy and may require colectomy. CDADmust be considered in all patients who present with diarrheafollowing antibiotic use. Careful medical history is necessary sinceCDAD has been reported to occur over two months after theadministration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directedagainst C. difficile may need to be discontinued. Appropriate fluid andelectrolyte management, protein supplementation, antibiotic treatmentof C. difficile, and surgical evaluation should be instituted as clinicallyindicated. [see Adverse Reactions]

Development of Drug-Resistant Bacteria: Prescribing DORIBAXTM inthe absence of a proven or strongly suspected bacterial infection isunlikely to provide benefit to the patient and increases the risk of thedevelopment of drug-resistant bacteria.

Pneumonitis with Inhalational Use: When DORIBAXTM has been usedinvestigationally via inhalation, pneumonitis has occurred.DORIBAXTM should not be administered by this route.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail inother sections of labeling:• Anaphylaxis and serious hypersensitivity reactions [see Warnings

and Precautions]• Interaction with sodium valproate [see Warnings and Precautions

and Drug Interactions]• Clostridium difficile-associated diarrhea [see Warnings and

Precautions]• Development of drug-resistant bacteria [see Warnings and

Precautions]• Pneumonitis with inhalational use [see Warnings and Precautions]

Adverse Reactions from Clinical Trials: Because clinical trials areconducted under widely varying conditions, adverse reaction ratesobserved in clinical trials of a drug cannot be compared directly torates from clinical trials of another drug and may not reflect ratesobserved in practice.

During clinical investigations, 853 adult patients were treated withDORIBAXTM IV (500 mg administered over 1 hour q8h) in the threecomparative phase 3 clinical studies; in some patients, parenteraltherapy was followed by a switch to an oral antimicrobial. [seeClinical Studies (14) in full Prescribing Information] The median age ofpatients treated with DORIBAXTM was 54 years (range 18-90) in thecomparative cUTI study and 46 years (range 18-94) in the pooledcomparative cIAI studies. There was a female predominance (62%) in

the comparative cUTI study and a male predominance (63%) in thepooled cIAI studies. The patients treated with DORIBAXTM werepredominantly Caucasian (77%) in the three pooled phase 3 studies.

The most common adverse reactions (≥ 5%) observed in theDORIBAXTM phase 3 clinical trials were headache, nausea, diarrhea,rash and phlebitis. During clinical trials, adverse drug reactions thatled to DORIBAXTM discontinuation were nausea (0.2%), vulvomycoticinfection (0.1%) and rash (0.1%).

Adverse reactions due to DORIBAXTM 500 mg q8h that occurred at arate ≥1 % in either indication are listed in Table 1. Hypersensitivityreactions related to intravenous study drug and C. difficile colitisoccurred at a rate of less than 1% in the three controlled phase 3clinical trials.

Table 1: Adverse Reactions† with Incidence Rates (%) of ≥1% andAdverse Events†† Having Clinically Important Differences inFrequency by Indication in the Three Controlled,Comparative DORIBAXTM Phase 3 Clinical Trials

Complicated Urinary Complicated Intra- Tract Infections Abdominal Infections

(one trial) (two trials)

System DORIBAXTM Levofloxacin DORIBAXTM Meropenemorgan 500 mg 250 mg IV 500 mg 1 g class q8h q24h q8h q8h

(n =376 ) (n = 372) (n = 477) (n = 469)

Nervoussystemdisorders

Headache 16 15 4 5

Vascular disorders

Phlebitis 4 4 8 6

Gastro-intestinaldisorders

Nausea 4 6 12 9Diarrhea 6 10 11 11

Blood and Lymphatic SystemDisorders

Anemia†† 2 1 10 5

Renal and UrinaryDisorders

Renalimpairment/Renal failure†† <1 0 1 <1

Skin and subcutaneousdisorders

Pruritus <1 1 3 2Rash* 1 1 5 2

InvestigationsHepatic enzyme

elevation** 2 3 1 3

Infection and Infestations

Oral candidiasis 1 0 1 2Vulvomycotic

infection 2 1 1 <1* includes reactions reported as allergic and bullous dermatitis,

erythema, macular/papular eruptions, urticaria and erythemamultiforme

** includes reactions reported as alanine aminotransferaseincreased, aspartate aminotransferase increased, hepatic enzymeincreased, and transaminases increased

† An adverse drug reaction was defined as an undesirable effect,reasonably associated with the use of DORIBAXTM that may occuras part of its pharmacological action or may be unpredictable in itsoccurrence.

†† An adverse event refers to any untoward medical event associatedwith the use of the drug in humans, whether or not considered drug-related.

Postmarketing Experience: The following adverse reactions havebeen identified during post-approval use of doripenem outside of theU.S. Because these reactions were reported voluntarily from apopulation of uncertain size, it is not possible to reliably estimate theirfrequency or establish a causal relationship to drug exposure.

AnaphylaxisNeutropenia

The following treatment-emergent adverse events (known to occurwith beta-lactams including carbapenems) have been reportedvoluntarily during post-approval use of DORIBAXTM outside of the U.S.They are included due to their seriousness, although it is not possibleto estimate their frequency and causality has not been established:

Stevens Johnson SyndromeToxic epidermal necrolysisInterstitial pneumoniaSeizure

DRUG INTERACTIONSValproic Acid: A clinically significant reduction in serum valproic acidconcentrations has been reported in patients receiving carbapenemantibiotics and may result in loss of seizure control. Although themechanism of this interaction is not fully understood, data from in

vitro and animal studies suggest that carbapenem antibiotics mayinhibit valproic acid glucuronide hydrolysis. Serum valproic acidconcentrations should be monitored frequently after initiatingcarbapenem therapy. Alternative antibacterial or anticonvulsanttherapy should be considered if serum valproic acid concentrationscannot be maintained in the therapeutic range or a seizure occurs.[see Warnings and Precautions]

Probenecid: Probenecid interferes with the active tubular secretion ofdoripenem, resulting in increased plasma concentrations ofdoripenem. [see Clinical Pharmacology (12.3) in full PrescribingInformation] Coadministration of probenecid with DORIBAXTM is notrecommended.

USE IN SPECIFIC POPULATIONSPregnancy: Category B: Doripenem was not teratogenic and did notproduce effects on ossification, developmental delays or fetal weightfollowing intravenous administration during organogenesis at dosesas high as 1 g/kg/day in rats and 50 mg/kg/day in rabbits (based onAUC, at least 2.4 and 0.8 times the exposure to humans dosed at 500mg q8h, respectively). There are no adequate and well-controlledstudies in pregnant women. Because animal reproduction studies arenot always predictive of human response, this drug should be usedduring pregnancy only if clearly needed.

Nursing Mothers: It is not known whether this drug is excreted inhuman milk. Because many drugs are excreted in human milk, cautionshould be exercised when DORIBAXTM is administered to a nursingwoman.

Pediatric Use: Safety and effectiveness in pediatric patients have notbeen established.

Geriatric Use: Of the total number of subjects in clinical studies ofDORIBAXTM, 28% were 65 and over, while 12% were 75 and over.Clinical cure rates in complicated intra-abdominal and complicatedurinary tract infections were slightly lower in patients ≥ 65 years ofage and also in the subgroup of patients ≥ 75 years of age versuspatients <65. These results were similar between doripenem andcomparator treatment groups.

No overall differences in safety were observed between older andyounger subjects, but greater sensitivity of some older individualscannot be ruled out.

Elderly subjects had greater doripenem exposure relative to non-elderly subjects; however, this increase in exposure was mainlyattributed to age-related changes in renal function. [see ClinicalPharmacology (12.3) in full Prescribing Information]

This drug is known to be excreted substantially by the kidney, and therisk of adverse reactions to this drug may be greater in patients withimpaired renal function or pre-renal azotemia. Because elderlypatients are more likely to have decreased renal function or pre-renalazotemia, care should be taken in dose selection, and it may be usefulto monitor renal function.

Patients with Renal Impairment: Dosage adjustment is required inpatients with moderately or severely impaired renal function. [seeDosage and Administration (2.2) and Clinical Pharmacology (12.3) infull Prescribing Information] In such patients, renal function shouldbe monitored.

PATIENT COUNSELING INFORMATION• Patients should be advised that allergic reactions, including

serious allergic reactions, could occur and that serious reactionsrequire immediate treatment. They should report any previoushypersensitivity reactions to DORIBAXTM, other carbapenems,beta-lactams or other allergens.

• Patients should be counseled that anti-bacterial drugs includingDORIBAX™ should only be used to treat bacterial infections.They do not treat viral infections (e.g., the common cold). WhenDORIBAX™ is prescribed to treat a bacterial infection, patientsshould be told that although it is common to feel better early inthe course of therapy, the medication should be taken exactly asdirected. Skipping doses or not completing the full course oftherapy may (1) decrease the effectiveness of the immediatetreatment and (2) increase the likelihood that bacteria willdevelop resistance and will not be treatable by DORIBAX™ orother antibacterial drugs in the future.

• Keep out of the reach of children.

MINI-BAG Plus is a trademark of Baxter International Inc.

Manufactured by: Shionogi & Co. Ltd.Osaka 541-0045, Japan

Distributed by: Ortho-McNeil Pharmaceutical, Inc.Raritan, NJ 08869

January 2008

10157601B

BREAK THROUGHUNLEASH THE POTENCY

* DORIBAXTM is indicated as a single agent for the treatment of complicated intra-abdominal infections caused by susceptible strains of E coli, K pneumoniae, P aeruginosa, B caccae, B fragilis, B thetaiotaomicron, B uniformis, B vulgatus, S intermedius, S constellatus, or P micros.

† DORIBAXTM is indicated as a single agent for the treatment of complicated urinary tract infections caused by susceptible strains of E coli, including cases with concurrent bacteremia,K pneumoniae, P mirabilis, P aeruginosa, or A baumannii.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of DORIBAXTM and other antibacterial drugs, DORIBAXTM should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting and modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Important Safety Information

DORIBAXTM is contraindicated in patients with known serious hypersensitivity to doripenem or other carbapenems, or in patients who have demonstrated anaphylactic reactions to beta lactams.Serious and occasionally fatal hypersensitivity (anaphylactic) and serious skin reactions have been reported in patients receiving beta-lactam antibiotics. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens. If an allergic reaction to DORIBAXTM occurs, discontinue the drug.

Serious acute anaphylactic reactions require emergency treatment with epinephrine and other emergency measures, including oxygen, IV fl uids, IV antihistamines, corticosteroids, pressor amines and airway management, as clinically indicated.Carbapenems may reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations cannot be maintained in the therapeutic range or seizures occur.Clostridium diffi cile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents and may range in severity from mild diarrhea to fatal colitis. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after administration of antibacterial agents. If CDAD is suspected or confi rmed, ongoing antibiotic use not directed against C diffi cile may need to be discontinued.When doripenem has been used investigationally via inhalation, pneumonitis has occurred. DORIBAXTM should not be administered by this route.Safety and effectiveness in pediatric patients have not been established.The most common adverse reactions (≥5%) observed in clinical trials were headache, nausea, diarrhea, rash, and phlebitis.

REFERENCES: 1. Evangelista AT, Yee C, Pillar CM, Aranza-Torres MK, Sahm DF, Thornsberry C. Surveillance profi ling of doripenem activity against Pseudomonas aeruginosa isolated from inpatients and ICU patients: results of the TRUST surveillance initiative. Presented at the 45th Annual Meeting of the Infectious Diseases Society of America (IDSA); 2007: San Diego, CA. 2. Data on fi le. Ortho-McNeil-Janssen Pharmaceuticals, Inc. 3. Jones ME, Draghi DC, Brown NP, Aranza MK, Thornsberry C, Sahm DF, et al. Baseline surveillance profi le of Doripenem (DOR) against key gram-negative pathogens encountered in the United States. Presented at the 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 2006:San Francisco, CA.

For more information, visit us at www.doribax.com

Clinical effi cacy proven in complicated intra-abdominal infections* and complicated urinary tract infections, including pyelonephritis†

Demonstrated safety and tolerability profi les—no seizures reported in 4 large Phase III clinical trials

Carbapenem potency that breaks through today’s gram-negative pathogens‡1-3

Proven in vitro activity vs P aeruginosa, Enterobacteriaceae, and A baumannii1-3

‡ In vitro activity does not necessarily correlate with clinical results.

Please see brief summary of full Prescribing Information on following pages.

© Ortho-McNeil-Janssen Pharmaceuticals, Inc. 2008 June 2008 02B07140TR3

ACCP Unveils Updated Thrombosis Close Call Guidelines

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